Arylalkylamine Compound and Process for Preparing the Same

ABSTRACT

The present invention relates to an arylalkylamine compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, a process for preparing the same, and use of the above-mentioned compound as an activating compound (CaSR agonist) of a Ca sensing receptor, a pharmaceutical composition containing the above-mentioned compound as an effective ingredient, etc.  
                 
The symbols in the formula represent the following meanings: Ar: optionally substituted aryl or optionally substituted heteroaryl here, the cyclic portion of the heteroaryl is bicyclic heterocyclic ring in which 5- to 6-membered monocyclic heterocyclic ring containing 1 or 2 hetero atom(s) and benzene ring are fused; 
         R 1 : a group selected from the group consisting of optionally substituted cyclic hydrocarbon group, and optionally substituted heterocyclic group; n: an integer of 1 to 3;    X: single bonding arm, —CH 2 —, —CO—, —(CH 2 ) m —CO—, —CH(R 2 )—CO—, —(CH 2 ) p —Y—(C(R 3 )(R 4 )) q —CO—, —NH—CO— or —N(R 5 )—CO—;    in the above-mentioned respective definitions of the X, the bonding arm described at the left end represents a bond with R 1 ; m is an integer of 1 to 3; p is an integer of 0 to 2; q is an integer of 0 to 2;    Y: —O— or —SO 2 —;    R 2 : phenyl or lower alkyl;    R 3 , R 4 : each independently represents hydrogen atom or lower alkyl;    R 5 : lower alkyl;    provided that the ring portion of the group represented by R 1  is neither naphthylidine nor partially saturated group thereof, and, when X is —CH 2 — or —CO—, R 1  is not naphthyl.

TECHNICAL FIELD

The present invention relates to a novel arylalkylamine compound whichhas activating effect on Ca sensing receptor (CaSR) and useful as amedicament, and a process for preparing the same.

BACKGROUND ART

Parathyroid hormone (PTH) is a hormone having a physiological functionwhich induces bone absorption to increase calcium (Ca) in blood, and hasa role of maintaining homeostasis of Ca in blood. When hypersecretion ofPTH is chronically continued, release of Ca from bone is continuedwhereby Ca concentration in blood increases and metabolic abnormalityoccurs. Thus, secretion and synthesis of PTH are strictly regulated bysignal transmission through Ca sensing receptor (CaSR) which sensesextracellular calcium ion (Ca²⁺) concentration.

Ca sensing receptor (CaSR) is one of G protein-coupled receptors, andexpressed on the surface of parathyroid cells, etc. When a compound(agonist) which activates the receptor binds to the receptor, it hasbeen known that Ca² concentration in cells increases, and secretion ofPTH from the cells of parathyroid is suppressed.

-   [Non-Patent Literature 1] Brown et al., Nature, 366:575-580, 1993;-   [Non-Patent Literature 2] Nemeth et al., Proc. Natl. Acad. Sci. USA,    95:4040-4045, 1998);-   [Non-Patent Literature 3] Brown, Annu. Rev. Nutr., 20:507-533, 2000;-   [Non-Patent Literature 4] Chattopadhyay, The International Journal    of Biochemistry & Cell Biology, 32:789-804, 2000; and-   [Non-Patent Literature 5] Coburn et al., Curr. Opin. Nephrol.    Hypertens., 9:123-132, 2000).

A compound having an activating effect on CaSR (CaSR agonist), that is,a compound which selectively acts on CaSR to mimic or strengthen theaction of Ca²⁺ is also called as calcimimetics. On the other hand, acompound having an antagonistic effect on CaSR (CaSR antagonist), thatis, a compound which suppresses or inhibits the action of Ca² is alsocalled as calcilytics.

With regard to CaSR agonist (calcimimetics) or CaSR antagonist(calcilytics), the following reports have been made. For example, inWO93/04373, WO94/18959, WO95/11221, WO96/12697, WO97/41090, WO98/01417,WO00/21910, WO01/34562, WO02/12181), WO01/90069, WO03/99814 andWO03/99776, amine derivatives having an activating effect orantagonistic effect on CaSR have been disclosed. It has been alsoreported that a compound having an activating effect on CaSR is expectedto show an ameliorating effect on hyperparathyroidism through loweringPTH concentration in blood.

The present invention is to provide a novel arylalkylamine compoundhaving an excellent Ca sensing receptor (CaSR) activating effect and aprocess for preparing the same.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

To solve the problems, the present inventors have conducted extensivestudies and as a result, they have found an arylalkylamine compoundhaving excellent CaSR activating effect whereby the present inventionhas been accomplished.

That is, the present invention relates to an arylalkylamine compoundrepresented by the formula [I]:

-   -   [The symbols in the formula represent the following meanings.    -   Ar: represents optionally substituted aryl or        -   optionally substituted heteroaryl,        -   here, the cyclic portion of the heteroaryl is a bicyclic            heterocyclic ring in which 5- to 6-membered monocyclic            heterocyclic ring containing 1 or 2 hetero atom(s) and            benzene ring are fused;    -   R¹: represents a group selected from the group consisting of        -   optionally substituted cyclic hydrocarbon group, and        -   optionally substituted heterocyclic group;    -   n: is an integer of 1 to 3;    -   X: represents single bonding arm, —CH₂—, —CO—,        -   —(CH₂)_(m)—CO—,        -   —CH(R²)—CO—,        -   —(CH₂)_(p)—Y— (C(R³)(R⁴))_(q)—CO—,        -   —NH—CO— or —N(R⁵)—CO—;    -   in the above-mentioned respective definitions of the X, the        bonding arm described at the left end represents a bond with R¹;    -   m is an integer of 1 to 3;    -   p is an integer of 0 to 2;    -   q is an integer of 0 to 2;    -   Y: represents —O— or —SO₂—;    -   R²: represents phenyl or lower alkyl;    -   R³, R⁴: each independently represents hydrogen atom or lower        alkyl;    -   R⁵: represents lower alkyl;    -   provided that the ring portion of the group represented by R¹ is        neither naphthylidine nor partially saturated group thereof,        and, when X is —CH₂— or —CO—, R¹ is not naphthyl.]        or a pharmaceutically acceptable salt thereof.

Also, it relates to a pharmaceutical composition containing theabove-mentioned arylalkylamine compound represented by the formula [I]or a pharmaceutically acceptable salt thereof as an effectiveingredient.

Further, it relates to a method for treatment or prophylaxis comprisingadministering an effective amount of the above-mentioned compound [I] ora pharmaceutically acceptable salt thereof to a patient, and a use ofthe same for the preparation of a pharmaceutical composition containingthe above-mentioned compound [I] or a pharmaceutically acceptable saltthereof as an effective ingredient. Also, it relates to theabove-mentioned compound [I] or a pharmaceutically acceptable saltthereof, and a process for preparing the same.

Means to Solve the Problems

In the objective compound [I] of the present invention, plural opticalisomers may be present (for example, among the compound [I], when n is 2or 3, there exists an optical isomer in which the carbon atom at the3-position of the nitrogen-containing cyclic structure portion is anasymmetric center). The present invention includes any of these isomers,and also includes a mixture thereof.

In the present invention, as the lower alkyl, the lower alkylthio, thelower alkylsulfonyl group, the lower alkoxy or the lower alkylamino,linear or branched ones having 1 to 6 carbon atoms may be mentioned, andparticularly those having 1 to 4 carbon atoms may be mentioned.

Also, as the lower alkanoyl or the lower alkanoylamino, those having 2to 7 carbon atoms, particularly those having 2 to 5 carbon atoms may bementioned.

As the lower alkanoyl, either of lower alkyl-CO— or lower cycloalkyl-CO—is included.

As the lower cycloalkyl or the lower cycloalkenyl, those having 3 to 8carbon atoms, particularly those having 3 to 6 carbon atoms may bementioned.

As the lower alkylene, linear or branched ones having 1 to 6 carbonatoms, particularly having 1 to 4 carbon atoms may be mentioned.

As the lower alkenyl or the lower alkenylene, those having 2 to 7 carbonatoms, particularly those having 2 to 5 carbon atoms may be mentioned.

Moreover, as the halogen atom, fluorine, chlorine, bromine or iodine maybe mentioned.

Also, as the optionally substituted amino group, cyclic amino(1-pyrrolidinyl, 1-piperidyl, 1-piperazinyl, 4-morpholinyl, etc.) isincluded.

In the objective compound [I] of the present invention, as the arylportion of the “optionally substituted aryl” represented by Ar,monocyclic or bicyclic aryl may be mentioned.

More specifically, for example, phenyl, naphthyl, etc., may bementioned.

As the heteroaryl portion of the “optionally substituted heteroaryl”represented by Ar, there may be mentioned bicyclic heterocyclic groupcomprising a monocyclic 5- to 6-membered hetero ring containing 1 or 2hetero atoms (selected from oxygen atom, sulfur atom and nitrogen atom)and a benzene ring being fused.

More specifically, for example, benzothienyl, etc., may be mentioned.

As substituent(s) of the “optionally substituted aryl” or the“optionally substituted heteroaryl” represented by Ar, halogen (F, Cl,Br, etc.), hydroxy, cyano, halo-lower alkyl, lower alkyl, lower alkoxy,lower alkylthio, etc., may be mentioned.

Among these, lower alkoxy group (methoxy, ethoxy, etc.), lower alkyl(methyl, etc.), etc. are preferable.

As the cyclic hydrocarbon group portion of the “optionally substitutedcyclic hydrocarbon group” represented by R¹, there may be mentioned, forexample, monocyclic or bicyclic hydrocarbon group having 3 to 11 carbonatoms, which may be saturated partially or completely.

More specifically, there may be mentioned, for example, monocyclichydrocarbon group having 3 to 7 carbon atoms such as phenyl, cyclohexyl,cyclopentyl, cyclobutyl, cyclopropyl, etc., and bicyclic hydrocarbongroup having 9 to 11 carbon atoms such as indanyl, indenyl, naphthyl,tetrahydronaphthyl, etc.

Among these cyclic hydrocarbon group, preferred are monocyclichydrocarbon group such as phenyl, cyclohexyl, etc., and a bicyclichydrocarbon group such as indanyl, indenyl, etc.

Among these, the monocyclic hydrocarbon group is more preferred, andphenyl and cyclopropyl, etc. are particularly preferred.

As the heterocyclic group portion of the “optionally substitutedheterocyclic group” represented by R¹, there may be mentioned saturatedor unsaturated monocyclic or bicyclic hetero ring containing 1 or morehetero atoms selected from nitrogen atom, oxygen atom and sulfur atom.

As the monocyclic ones, there may be mentioned hetero ring comprisingsaturated or unsaturated 5 to 7-membered ring, and containing 1 to 4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,etc.

Also, as the bicyclic ones, there may be mentioned hetero ringcomprising two saturated or unsaturated 5 to 7-membered rings beingfused, and containing 1 to 6 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, etc.

As the monocyclic ones, more specifically, there may be mentioned, forexample, monocyclic group such as pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxolanyl, thiolanyl, pyrrolinyl, imidazolinyl,pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furyl, oxazolyl, isooxazolyl, oxadiazolyl, thienyl, thiazolyl,isothiazolyl, thiadiazolyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, pyridyl, pyrimidinyl, pyradinyl, pyridazinyl, pyranyl,perhydroazepinyl, perhydrothiazepinyl, partially or completely saturatedgroup thereof, and cyclic group in which hetero atom (N or S) of theabove is/are oxidized (pyridyl-N-oxide, etc.), etc.

Among these, pyrrolyl, thienyl, thiazolyl, piperazinyl, pyridyl,pyrimidinyl, pyradinyl, pyridazinyl, etc. are preferred.

Also, as the bicyclic ones, there may be mentioned, for example,bicyclic group such as indolinyl, isoindolinyl, indolyl, indazolyl,isoindolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, benzodioxolanyl, benzothienyl, benzofuryl, thienopyridyl,thiazolopyridyl, pyrrolopyridyl, pyrrolopyrimidinyl,cyclopentapyrimidinyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, phthalazinyl, cinnolinyl, chromanyl, isochromanyl,benzothiazinanyl, partially or completely saturated group thereof, andcyclic group in which a hetero atom (N or S) of the above is/areoxidized, etc.

Among these, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl,quinolyl, phthalazinyl, benzothiazinanyl, etc. are preferred.

As the heterocyclic group portion of the “optionally substitutedheterocyclic group” represented by R¹, among the above-mentionedmonocyclic and bicyclic ones, the monocyclic ones are more preferred.

As substituent(s) of the “optionally substituted cyclic hydrocarbongroup” or the “optionally substituted heterocyclic group” represented byR¹, for example, there may be mentioned those of the followingSubstituent group Q1.

<Substituent Group Q1>

halogen (Cl, F, Br, I, etc.)

cyano

nitro

oxo group

hydroxy

carboxy

optionally substituted lower alkyl

(which may be optionally substituted by 1 or plural groups selected fromhalogen, cyano, nitro, oxo, carboxy, hydroxy, lower alkoxy andhalo-lower alkoxy, etc.)

optionally substituted lower alkoxy

(which may be optionally substituted by 1 or plural groups selected fromhalogen, cyano, nitro, oxo, carboxy and hydroxy, etc.)

optionally substituted amino

(which may be optionally mono- or di-substituted by the group selectedfrom lower alkyl, halo-lower alkyl, etc.)

optionally substituted 5 to 6-membered monocyclic heterocyclic group(tetrazole, pyridazinyl, or partially saturated cyclic group thereof,etc.)

(which may be optionally substituted by 1 or plural groups selected fromhalogen, cyano, nitro, oxo, carboxy, hydroxy, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy and acyl, etc.)

optionally substituted phenyl

(which may be optionally substituted by 1 or plural groups selected fromhalogen, cyano, nitro, oxo, carboxy, hydroxy, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy and acyl, etc.)

acyl

[for example, optionally substituted lower alkanoyl

-   -   (which may be optionally substituted by 1 or plural groups        selected from halogen, cyano, nitro, oxo, carboxy and hydroxy,        etc.);

optionally substituted lower cycloalkylcarbonyl

-   -   (which may be optionally substituted by 1 or plural groups        selected from halogen, cyano, nitro, oxo, carboxy and hydroxy,        etc.);

optionally substituted lower alkylsulfonyl

-   -   (which may be optionally substituted by 1 or plural groups        selected from halogen, cyano, nitro, oxo, carboxy and hydroxy,        etc.);

esterified carbonyl

-   -   (lower alkoxycarbonyl which may be optionally substituted by 1        or plural groups selected from halogen, cyano, nitro, oxo,        carboxy and hydroxy, etc.; carbonyl substituted by a group of        D-glucuronic acid in which a hydrogen atom in hydroxy of its        2-position is eliminated, etc.);

optionally substituted aliphatic 5 to 6-membered nitrogen-containingheterocyclic group-CO— (pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, morpholinocarbonyl, etc.)

-   -   (which may be optionally substituted by 1 or plural groups        selected from halogen; cyano; oxo; hydroxy; carboxy; lower alkyl        which may be substituted by halogen, hydroxy, carboxy, lower        alkoxy or halo-lower alkoxy, etc.; carbamoyl; lower        alkylsulfonyl; and lower alkylsulfonylamino);

optionally substituted carbamoyl

-   -   (which may be mono- or di-substituted by group(s) selected from        the following Substituent group Q2); and;

optionally substituted aminosulfonyl

-   -   (which may be mono- or di-substituted by group(s) selected from        the following Substituent group Q2); etc.]        <Substituent Group Q2>

optionally substituted lower alkyl

-   -   [which may be optionally substituted by 1 or plural groups        selected from halogen; hydroxy; carboxy; aryl (phenyl, etc.);        lower cycloalkyl; lower alkoxy; mono- or di-lower alkylamino;        lower alkanoylamino; aliphatic nitrogen-containing 5 to        6-membered heterocyclic group (pyrrolidinyl, piperidinyl,        morpholinyl, etc.) which may be substituted by oxo, etc.; and an        acyl (lower alkanoyl, lower alkoxycarbonyl, carbamoyl,        morpholinocarbonyl, etc.); etc.];

optionally substituted lower cycloalkyl

-   -   (which may be optionally substituted by 1 or plural groups        selected from hydroxy; hydroxyl lower alkyl; and aliphatic        nitrogen-containing 5 to 6-membered heterocyclic group        (pyrrolidinyl, piperidinyl, morpholinyl, etc.) which may be        substituted by oxo, etc.; etc.);

optionally substituted aliphatic nitrogen-containing 5 to 6-memberedheterocyclic group (piperidinyl, etc.)

-   -   [which may be optionally substituted by 1 or plural groups        selected from lower alkyl and acyl (lower alkanoyl, lower        alkylsulfonyl, lower alkoxycarbonyl, mono or di-lower        alkylaminosulfonyl, mono or di-lower alkylaminocarbonyl, etc.),        etc.]; and tetrahydropyranyl.

When R¹ is optionally substituted phenyl, the substituent(s) maydesirably be carboxy, halogen (F, Cl, etc.), unsubstituted orsubstituted lower alkyl (carboxy-lower alkyl, halo-lower alkyl, etc.),unsubstituted or substituted lower alkoxy (halo-lower alkoxy, etc.),acyl (lower alkylsulfonyl, carbamoyl, hydroxyl-lower alkylcarbamoyl,lower alkylaminosulfonyl, mono- or di-lower alkylamino loweralkylaminosulfonyl, etc.), or optionally substituted 5 to 6-memberedmonocyclic heterocyclic group (tetrazole or partially saturated groupthereof, etc.), etc.

As the “lower alkyl” represented by R², methyl or ethyl is preferred.

As the “lower alkyl” represented by R³ and R⁴, methyl or ethyl ispreferred.

As the “lower alkyl” represented by R⁵, methyl or ethyl is preferred.

Among the compound [I] of the present invention, as a preferred ones,there may be mentioned a compound having the following partialstructure:

that is,a compound represented by the formula [I-e]:

[the symbols in the formula have the same meanings as mentioned above].

More preferred compound groups are those wherein X is single bondingarm, —CO— or —(CH₂)_(m)—CO—. More preferred compounds are those whereinn is 1 or 2, and X is single bonding arm, —CO— or —(CH₂)_(m)—CO—.

Or else, there may be mentioned compound groups wherein n is 2, and X issingle bonding arm.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein Ar is optionally substituted aryl.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein Ar is optionally substituted phenyl oroptionally substituted naphthyl.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein Ar is a group optionally substitutedby group(s) selected from halogen, hydroxy, cyano, halo-lower alkyl,lower alkyl, lower alkoxy and lower alkylthio.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein Ar is a group optionally substitutedby group(s) selected from lower alkyl and lower alkoxy.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein the ring portion of the grouprepresented by R¹ is cyclic hydrocarbon group, or monocyclicheterocyclic group.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein the cyclic group portion of the grouprepresented by R¹ is the following (i), (ii) or (iii).

(i) monocyclic or bicyclic hydrocarbon group having 3 to 11 carbonatoms, which may be saturated partially or completely;

(ii) a monocyclic heterocyclic group, the hetero ring of which comprisesone saturated or unsaturated 5 to 7-membered ring, and contains 1 to 4hetero atom(s) selected from nitrogen atom, oxygen atom and sulfur atom;or

(iii) bicyclic heterocyclic group, the hetero ring of which comprisestwo saturated or unsaturated 5 to 7-membered rings being fused, andcontain 1 to 6 hetero atom(s) selected from nitrogen atom, oxygen atomand sulfur atom.

Further, in any one of the above-mentioned compound groups, there may bementioned compound groups wherein the cyclic group portion of the grouprepresented by R¹ is the following (i), (ii) or (iii).

(i) monocyclic or bicyclic hydrocarbon group selected from phenyl,cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, indanyl, indenyl,naphthyl, tetrahydronaphthyl, and partially or completely saturatedgroup thereof;

(ii) monocyclic heterocyclic group selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxolanyl, thiolanyl, pyrrolinyl,imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, furyl, oxazolyl, isooxazolyl, oxadiazolyl, thienyl,thiazolyl, isothiazolyl, thiadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyradinyl,pyridazinyl, pyranyl, perhydroazepinyl, perhydrothiazepinyl, partiallyor completely saturated group thereof, and a group in which the heteroatom(s) (N or S) thereof is/are oxidized; or

(iii) bicyclic heterocyclic group selected from indolinyl, isoindolinyl,indolyl, indazolyl, isoindolyl, benzimidazolyl, benzotriazolyl,benzothiazolyl, benzoxazolyl, benzodioxolanyl, benzothienyl, benzofuryl,thienopyridyl, thiazolopyridyl, pyrrolopyridyl, pyrrolopyrimidinyl,cyclopentapyrimidinyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, phthalazinyl, cinnolinyl, chromanyl, isochromanyl,benzothiazinanyl, partially or completely saturated group thereof, and agroup in which the hetero atom(s) (N or S) thereof is/are oxidized.

The compound [I] of the present invention may be in a free form or in aform of pharmaceutically acceptable salt.

As the pharmaceutically acceptable salt, there may be mentioned, forexample, inorganic acid salt such as hydrochloride, sulfate, nitrate,phosphate or hydrobromide, etc., organic acid salt such as acetate,fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate,p-toluenesulfonate or maleate, etc. Also, when the compound has asubstituent such as carboxyl group, etc., there may be mentioned a saltwith a base (for example, alkali metal salt such as sodium salt,potassium salt, etc. or alkaline earth metal salt such as calcium salt,etc.).

The compound [I] or a salt thereof of the present invention includes anyof its intramolecular salt or adduct, or its solvate or hydrate, etc.

The objective Compound [I] (particularly Compound [I-e]) or apharmaceutically acceptable salt thereof according to the presentinvention has an excellent CaSR activating effect. The pharmaceuticalcomposition containing the objective compound of the present inventionas an effective ingredient is useful as an effective ingredient of amedicament for treatment or prophylaxis of diseases of which conditionis expected to be improved by activation of CaSR and/or suppression ofPTH production (and/or lowering of PTH level in blood through the same)[for example, hyperparathyroidism (primary hyperparathyroidism,secondary hyperparathyroidism and ectopic hyperparathyroidism, etc.),etc.].

The objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention has an excellent activating effect on CaSR.Also, it has high selectivity on CaSR.

Moreover, the objective compound [I] or a pharmaceutically acceptablesalt thereof of the present invention shows various kinds ofpharmacological effects through its activating effect on CaSR, in whichproduction of PTH is suppressed, PTH level in blood is lowered in aliving body, etc. Accordingly, the pharmaceutical composition containingthe objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention as an effective ingredient can be used foractivating CaSR. Also, the pharmaceutical composition can be used forsuppressing production of PTH. Also, it can be used for lowering PTHlevel in blood in a living body. Also, the pharmaceutical compositioncan be used for treatment or prophylaxis of diseases of which conditionis expected to be improved by activation of CaSR and/or suppression ofPTH production (and/or lowering of PTH level in blood through the same).

The compounds having an activating effect on CaSR have been known toshow ameliorating effect on hyperparathyroidism through lowering of PTHconcentration in blood as shown in, for example, WO93/04373, WO94/18959,WO95/11221, WO96/12697, WO97/41090, WO98/01417, WO03/99814 andWO03/99776.

Accordingly, the pharmaceutical composition containing as an effectiveingredient the objective compound [I] or a pharmaceutically acceptablesalt thereof of the present invention can be used for treatment orprophylaxis of diseases of which condition is expected to be improved byactivation of CaSR and/or suppression of PTH production (and/or loweringof PTH level in blood through the same), i.e., hyperparathyroidism(primary hyperparathyroidism, secondary hyperparathyroidism and ectopichyperparathyroidism, etc.), and the like.

A method of administering to a patient an effective amount of thecompound [I] or a pharmaceutically acceptable salt thereof of thepresent invention, and a use for the preparation of the pharmaceuticalcomposition containing as an effective ingredient the compound [I] or apharmaceutically acceptable salt thereof of the present invention areapplied to the above-mentioned objects, and included in the presentinvention.

Pharmacological effects such as an activating effect on CaSR andsuppressing effect on PTH-production, etc. of the compounds of thepresent invention can be confirmed by the known methods (WO97/37967,WO93/04373, WO94/18959, WO97/41090, Nemeth et al., Proc. Natl. Acad. SciUSA, 95:4040-4045, 1998; Racke and Nemeth, J. Physiol., 468: 163-176,1993; and Nemeth et al., J. Pharmacol. Exp. Ther. 308:627-635, 2004), oran equivalent method thereto.

Also, for the test of the suppressing effect on PTH-production, forexample, there may be suitable used a method in which an effect of atest compound is assayed by using parathyroid cells of rats.

This method contains the following steps.

(i) Primary culture parathyroid cells of rat are prepared.

(Parathyroid cells are collected from rats and they are subjected toprimary culture.)

(ii) The cells of (i) are incubated under the conditions of low calciumconcentration [for example, in a medium with Ca concentration of about1.5 mM or less (preferably 1.15 mM or less), etc.], in the presence ofvarious concentrations of a test substance (or in the presence andabsence of the test substance).

(iii) PTH production level is compared in the presence of variousconcentrations of the test substance.

(or PTH production level in the presence and absence of the testsubstance is compared.)

(iv) From the results of (iii), strength of an effect

(suppressing effect or strengthening effect) of the test substance onthe PTH production, or presence or absence of the effect of the same isdetermined.

In more detail, it can be carried out in the same manner as mentioned inthe following Experimental example 2.

According to this method, preparation of cells is easy as compared withthe conventional method using parathyroid cells of big animals (bovine,etc.). Also, change in PTH production can be observed with incubationfor a suitable period of time, so that the test can be carried outstably and efficiently. Moreover, it enables a test for a large numberof test substances.

Furthermore, it is advantageous for selecting a substance which showspotent effect in a living body by using cells of an animal (rat) whichis the same as disease model usually employed in in vivo test.

PTH level lowering effect in living body can be detected by in vivo testusing a known animal model (disease model of hyperparathyroidism, etc.).

As such an animal model, there may be applied, for example, rat adeninemodel, rat model of ⅚-nephrectomy, etc., more specifically, for example,the method described in the following mentioned Experimental examples 3and 4, etc., may be applied to.

When the compound [I] or a pharmaceutically acceptable salt thereof ofthe present invention is used as an effective ingredient for medicaluse, it can be used with an inert carrier suitable for eachadministration method, and can be formulated into conventionalpharmaceutical preparation (tablets, granules, capsules, powder,solution, suspension, emulsion, injection, infusion, etc.). As such acarrier, there may be mentioned, for example, a binder (Gum Arabic,gelatin, sorbitol, polyvinylpyrrolidone, etc.), an excipient (lactose,sugar, corn starch, sorbitol, etc.), a lubricant (magnesium stearate,talc, polyethylene glycol, etc.), a disintegrator (potato starch, etc.)and the like, which are pharmaceutically acceptable. When they are usedas an injection solution or an infusion solution, they can be formulatedby using distilled water for injection, physiological saline, an aqueousglucose solution, etc.

An administration method of the compound [I] or a pharmaceuticallyacceptable salt thereof of the present invention to be used for medicaluse is not particularly limited, and a usual oral or parenteraladministration method (intravenous, intramuscular, subcutaneous,percutaneous, intranasal, and as others, transmucosal, enteral, etc.)can be applied to.

The dosage of the compound [I] or a pharmaceutically acceptable saltthereof of the present invention to be used for medical use may beoptionally set in a range of an effective amount sufficient for showinga pharmacological effect, in accordance with the potency orcharacteristics of the compound to be used as an effective ingredient.The dosage may vary depending on an administration method, or an age, abody weight or conditions of a patient, and a usual dosage is set, forexample, to a suitable amount in the range of 0.001 to 300 mg/kg perday.

The objective compound [I] of the present invention can be prepared bythe following [Method A], [Method B], [Method C], [Method D], [MethodE], [Method F], but the present invention is not limited by these.

(wherein Z¹ represents a reactive residue, and the other symbols havethe same meanings as defined above.)

Among the objective compounds [I] of the present invention, the compoundrepresented by the formula [I-a] wherein X is single bonding arm can beprepared, for example, as follows.

First, the compound represented by the formula [11] or a salt thereof isreacted with the compound represented by the formula [12], and ifdesired, the resulting compound is converted into a pharmaceuticallyacceptable salt thereof to obtain the objective Compound [I-a].

As the reactive residue represented by Z¹, a conventionally usedreactive residue such as halogen atom, lower alkylsulfonyloxy group,arylsulfonyloxy group, etc., can be suitably used, and halogen atom isparticularly preferred.

As a salt of Compound [11], there may be used, for example, a salt withan inorganic acid such as hydrochloride, sulfate, etc.

The reaction in the above-mentioned Method A can be carried out, forexample, as shown in the following Reaction A1, or Reaction A2.

Reaction A1:

The reaction of Compound [11] or a salt thereof and Compound [12] can becarried out, for example, in a suitable solvent, and in the presence ofa catalyst and a base.

As the catalyst, there may be suitably used a palladium catalyst [forexample, palladium acetate, trisdibenzylideneacetone dipalladium, etc.].

Further, in order to accelerate the reaction, a trivalent phosphoruscompound such as triphenylphosphine, BINAP(2,21-bis(di-phenylphosphino-1,1′-binaphthyl)),biphenyl-2-yl-di-tert-butylphosphane, etc., may be added. Particularly,when a divalent palladium catalyst (palladium acetate, etc.) having noligand is used as a catalyst, a trivalent phosphorous compound is added.

As the base, there may be suitably used, for example, cesium carbonate(Cs₂CO₃), sodium butoxide, an alkali metal amide (lithiumhexamethyldisilazide, potassium hexamethyldisilazide, sodiumhexamethyldisilazide, etc.), etc.

The present reaction suitably proceeds at 0 to 150° C., particularly atroom temperature to 120° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, tert-butanol,tetrahydrofuran, dioxane, toluene, 1-methyl-2-pyrrolidinone,1,2-dimethoxyethane, diglyme, xylene or a mixture thereof.

Reaction A2:

The reaction of Compound [11] or a salt thereof and Compound [12] can becarried out, for example, in a suitable solvent in the presence of abase.

As such a base, there may be suitably used an inorganic base (forexample, alkali metal hydride such as sodium hydride, etc., alkali metalcarbonate such as sodium carbonate, potassium carbonate, etc., alkalimetal alkoxide such as sodium butoxide, sodium methoxide, etc.) or anorganic base (for example, triethylamine, diisopropylethylamine,N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine,etc.), etc.

The present reaction suitably proceeds at 20 to 200° C., particularly at70 to 140° C.

As the solvent, there may be suitably used acetonitrile, methanol,ethanol, isopropyl alcohol, n-propyl alcohol, tert-butanol, acetone,N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane, ethyl acetate, toluene, methylene chloride,dichloroethane, chloroform, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone,1,2-dimethoxyethane, diglyme, xylene or a mixture thereof.

(wherein the symbols have the same meanings as defined above.)

Among the objective compound [I] of the present invention, the compoundrepresented by the formula [I-b] in which X is —CH₂— can be prepared,for example, as follows.

First, the compound represented by the formula [11] or a salt thereof isreacted with a compound represented by the formula [13], and if desired,the resulting compound is converted into a pharmaceutically acceptablesalt thereof to obtain the objective Compound [I-b].

As a salt of Compound [11], similar salts as mentioned above can beused.

The reaction of Compound [11] or a salt thereof and Compound [13] can becarried out in a suitable solvent in the presence of a reducing agent.

As the reducing agent, there may be suitably used sodiumtriacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc.

Further, in order to accelerate the reaction, an organic acid such asacetic acid, propionic acid, etc. is preferably added.

The present reaction suitably proceeds at 0 to 60° C., particularly at20 to 40° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,tetrahydrofuran, diethyl ether, dioxane, ethyl acetate, toluene,methylene chloride, dichloroethane, chloroform, 1,2-dimethoxyethane,xylene or mixture thereof. Among them, methylene chloride isparticularly preferably used.

[wherein X¹ represents —CO—, —(CH₂)_(m)—CO—, —CH(R²)—CO—,—(CH₂)_(p)—Y—(C(R³)(R⁴))_(q)—CO—, or —N(R⁵)—CO—, and other symbols havethe same meanings as defined above.]

Among the objective compounds [I] of the present invention, the compoundrepresented by the formula [I-c] wherein X is —CO—, —(CH₂)_(m)—CO—,—CH(R²)—CO—, —(CH₂)_(p)—Y—(C(R³)(R⁴))_(q)—CO—, or —N(R⁵)—CO— can beprepared, for example, as mentioned below.

First, the compound represented by the formula [11] or a salt thereof isreacted with the compound represented by the formula [14a] or [14b], andif desired, the resulting compound is converted into a pharmaceuticallyacceptable salt thereof to obtain the objective Compound [I-c].

As a salt of Compound [11], the same salt as mentioned above can beused.

The reaction of Compound [11] or a salt thereof and Compound [14a] canbe carried out in a suitable solvent in the presence of a base.

As such a base, an organic base (for example, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline,dimethylaminopyridine, etc.), etc. may be preferably used.

The present reaction suitably proceeds at −20 to 50° C., particularlypreferably at 10 to 30° C.

The solvent may be any one which does not shown an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,tetrahydrofuran, diethyl ether, dioxane, ethyl acetate, toluene,methylene chloride, dichloroethane, chloroform, 1,2-dimethoxyethane,xylene or a mixture thereof.

Also, the reaction of Compound [11] or a salt thereof and Compound [14b]can be carried out in a suitable solvent in the presence of a condensingagent, and if necessary in the presence or absence of an additive and/ora base.

As the condensing agent, there may be suitably usedO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate,DCC (dicyclohexylcarbodiimide), EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), chloroformic acidesters (for example, ethyl chloroformate, isobutyl chloroformate),carbonyldiimidazole, etc.

Further, in order to accelerate the reaction, an additive such as1-hydroxybenzotriazole, 1-hydroxysuccinimide, etc., or a base may beadded together with the above-mentioned condensing agent.

As such a base, there may be suitably used an organic base (for example,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine,dimethylaniline, dimethylaminopyridine, etc.), alkali metal carbonate(sodium carbonate, potassium carbonate, etc.), etc.

The present reaction suitably proceeds at 0 to 100° C., particularlypreferably at 20 to 50° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dioxane, ethylacetate, toluene, methylene chloride, dichloroethane, chloroform,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, xylene or a mixturethereof.

[the symbols in the formula have the same meanings as defined above.]

Among the objective compounds [I] of the present invention, the compoundrepresented by the formula [I-d] wherein X is —NH—CO— can be prepared,for example, as mentioned below.

First, the compound represented by the formula [11] or a salt thereof isreacted with the compound represented by the formula [15], and ifdesired, the resulting compound is converted into a pharmaceuticallyacceptable salt thereof to obtain the objective Compound [I-d].

As a salt of Compound [11], the same salt as mentioned above can beused.

The reaction of Compound [11] or a salt thereof and Compound [15] can becarried out in a suitable solvent in the presence or absence of a base.

As such a base, there may be suitably used an inorganic base (forexample, alkali metal hydride such as sodium hydride, etc., alkali metalcarbonate such as sodium carbonate, potassium carbonate, etc., alkalimetal alkoxide such as sodium butoxide, etc., alkali metal hydroxidesuch as sodium hydroxide, potassium hydroxide, etc.) or an organic base(for example, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, dimethylaniline, dimethylaminopyridine, etc.), etc.

The present reaction suitably proceeds at 0 to 60° C., particularlypreferably at 10 to 30° C.

The solvent may be any one which does not shown an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dioxane, ethylacetate, toluene, methylene chloride, dichloroethane, chloroform,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, xylene or a mixturethereof.

(wherein the symbols have the same meanings as defined above.)

The objective Compound [I-a] can be also prepared, for example, asfollows.

First, a compound represented by the formula [21] or a salt thereof isreacted with a compound represented by the formula [22] to obtain acompound represented by the formula [23]. This is applied to anoxidation reaction to obtain a compound represented by the formula [24].Compound [24] is reacted with a compound represented by the formula [25]or a salt thereof, and if desired, the resulting compound is convertedinto a pharmaceutically acceptable salt thereof to obtain the objectiveCompound [I-a].

As a salt of Compound [21] and [25], there may be used, for example, asalt with an inorganic acid such as a hydrochloride, a sulfate, etc.

The respective reactions in Method E can be carried out as follows.

The reaction of Compound [21] or a salt thereof and Compound [22] can becarried out in a suitable solvent and in the presence of a copperreagent.

As the copper reagent, copper acetate, etc. can be suitably used.

Further, in order to accelerate the reaction, a base is added. As such abase, there may be suitably used, for example, triethylamine, pyridine,etc.

Also, when water is mixed into the reaction system, the reaction rate islowered. Accordingly, to prevent such a matter, a dehydrating agent suchas Molecular Sieve 4A, etc. may be added in the reaction system.

The present reaction suitably proceeds at 0 to 40° C., particularlypreferably at 10 to 30° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, methylenechloride, dichloroethane or a mixture thereof, and, methylene chlorideis particularly suitable.

Oxidation reaction of Compound [23] can be carried out according to theconventional method, and it can be carried out, for example, in asuitable solvent in the presence of an oxidizing agent.

As the oxidizing agent, there may be suitably used oxalylchloride-dimethylsulfoxide, sulfur trioxide-pyridine complex, etc.

The present reaction suitably proceeds at −70 to 40° C., particularlypreferably at −70 to 20° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, methylenechloride, etc., when oxalyl chloride-dimethylsulfoxide is used as anoxidizing agent, and suitably used dimethylsulfoxide when sulfurtrioxide-pyridine complex is used as an oxidizing agent.

The reaction of Compound [24] and Compound [25] or a salt thereof can becarried out in the same manner as in the reaction of Compound [11] andCompound [13] in the above-mentioned Method B.

(wherein the symbols have the same meanings as defined above.)

The objective Compound [I-b] can be also prepared, for example, asfollows.

First, a compound represented by the formula [21] or a salt thereof isreacted with the above-mentioned Compound [13] to obtain a compoundrepresented by the formula [26]. This is applied to an oxidationreaction to obtain a compound represented by the formula [27]. Compound[27] is reacted with the above-mentioned Compound [25] or a saltthereof, and if desired, the resulting compound is converted into apharmaceutically acceptable salt thereof to obtain the objectiveCompound [I-b].

The respective reactions in Method F can be carried out as follows.

The reaction of Compound [21] or a salt thereof and Compound [13] can becarried out in the same manner as in the reaction of the above-mentionedCompound [11] and Compound [13].

The oxidation of Compound [26] can be carried out in the same manner asin the oxidation of the above-mentioned Compound [23].

The reaction of Compound [27] and Compound [25] or a salt thereof can becarried out in the same manner as in the reaction of the above-mentionedCompound [24] and Compound [25].

[Preparation Method of Starting Compound]

Compound [11] which is a starting compound in the above-mentioned MethodA, Method B, Method C and Method D can be prepared, for example, asfollows.

(wherein Q represents a protective group for amino group, and the othersymbols have the same meanings as defined above.)

First, a compound represented by the formula [31] or a salt thereof isreacted with the above-mentioned Compound [25] or a salt thereof toobtain a compound represented by the formula [33].

Or else, Compound [31] is applied to oxidation to obtain a compoundrepresented by the formula [32]. This is reacted with theabove-mentioned Compound [25] or a salt thereof to obtain Compound [33].

By removing a protective group for amino group from Compound [33],Compound [11] can be obtained.

As the protective group for amino group represented by Q, any of theconventionally used protective groups for amino group such ast-butoxycarbonyl group, benzyloxycarbonyl group, trifluoroacetyl group,9-fluorenylmethyloxycarbonyl group, etc. can be suitably used.

The respective reactions can be carried out as follows.

The reaction of Compound [31] and Compound [25] or a salt thereof can becarried out in a suitable solvent, in the presence of anhydroustrifluoromethanesulfonic acid, etc. and in the presence of a base. Assuch a base, there may be suitably used, for example, an organic basesuch as diisopropylethylamine, etc., and the like.

The present reaction suitably proceeds at −50° C. to room temperature,particularly preferably at −20° C. to room temperature.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,tetrahydrofuran, diethyl ether, dioxane, ethyl acetate, toluene,methylene chloride, dichloroethane, chloroform, 1,2-dimethoxyethane,xylene or a mixture thereof, and, particularly methylene chloride can besuitably used.

The oxidation of Compound [31] can be carried out in the same manner asin the oxidation of the above-mentioned Compound [23].

The reaction of Compound [32] and Compound [25] or a salt thereof can becarried out in the same manner as in the reaction of the above-mentionedCompound [24] and Compound [25].

Or else, it can be carried out by using titanium tetraisopropoxide, etc.as a condensing agent, and using sodium borohydride, etc., as a reducingagent.

Removal of the protective group for amino group (Q) from Compound [33]can be carried out in a conventional manner, and can be carried out, forexample, by an acid treatment, a base treatment or a catalyticreduction, in a suitable solvent or without a solvent.

When n is 2 or 3, in Compound [33] and Compound [11], there existoptical isomers in which the carbon atom at the 3-position of thenitrogen-containing ring is a chiral center.

Such optically active Compound [33] and Compound [11] can be preparedfrom a diastereomer mixture [33], for example, as follows.

First, Compound [33] is reacted with a phosgene, and the resultingproducts (diastereomer mixture) are purified and separated bycrystallization and/or column chromatography, if desired, to obtainoptically active compounds represented by the formula [34a] and formula[34b].

Or else, an optically active compounds can be similarly obtained byreacting a carbamoyl chloride diastereomer mixture with an alcohol(tert-butanol, etc.) and separating the resulting carbamate diastereomermixture using a column.

Compound [34a] or Compound [34b] is reacted with H₂O to obtain acompound represented by the formula [33a] and formula [33b].

By removing a protective group for amino group from Compound [33a] orCompound [33b], the compound represented by the formula [11a] or formula[11b] can be prepared.

The reaction of Compound [33] and a phosgene (triphosgene, diphosgene,carbonyldiimidazole, 4-nitrophenylchloroformate, etc.) can be carriedout in a suitable solvent in the presence of a base.

As such a base, there may be suitable used an organic base (for example,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine,dimethylaniline, dimethylaminopyridine, etc.), etc.

The present reaction suitably proceeds at −40 to 40° C., particularlypreferably at −20° C. to room temperature.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,tetrahydrofuran, diethyl ether, dioxane, ethyl acetate, toluene,methylene chloride, dichloroethane, chloroform, 1,2-dimethoxyethane,xylene or a mixture thereof, and, particularly, methylene chloride canbe suitably used.

The reaction of Compound [34a] or Compound [34b] and H₂O can be carriedout in a suitable solvent.

The present reaction suitably proceeds at room temperature to 120° C.,particularly preferably at 70 to 100° C.

The solvent may be any one which does not show an adverse affect on thereaction, and there may be suitably used, for example, acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane, ethyl acetate, toluene, methylene chloride,dichloroethane, chloroform, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone,1,2-dimethoxyethane, xylene or a mixture thereof.

Removal of the protective group for amino group (Q) from Compound [33a]or Compound [33b] can be carried out in the same manner as in theremoval of the protective group for amino group from the above-mentionedCompound [33].

Other starting compound can be prepared in the same manner according tothe known methods and/or the methods described in the followingReference examples.

Also, the objective Compound [I] prepared by the above-mentionedpreparation methods (Method A, Method B, Method C, Method D, Method E,Method F) can be further structurally converted into the other objectiveCompound [I] according to the methods described in the followingExamples and/or the known methods or combination thereof.

Compound [I] according to the present invention or a starting compoundthereof, prepared as mentioned above, can be isolated and purified as afree form or a salt thereof. The salt can be prepared by a conventionalmethod for preparation of a salt. Isolation and purification can becarried out by conventional chemical procedures such as extraction,concentration, crystallization, filtration, recrystallization, variouskinds of chromatography, etc.

EXAMPLE

In the following, the present invention is illustrated in more detail byExamples, but these Examples do not limit the present invention.

In Table A1, Table A2, Table B, Table CD, Table EF, Table X, Table Y andReference example Table at the end of the specification, chemicalstructures and physical properties, etc., of the compounds of Examplesand Reference examples are shown.

In Tables, MS·APCI (m/z) indicate mass spectrometric data (atmosphericpressure chemical ionization mass spectrum).

Moreover, in the abbreviations in the present specification are asfollows;

“Me” represents methyl group,

“Et” represents ethyl group, and

“Bu” represents butyl group, respectively.

Experimental Example 1 CaSR Activating Effect

In Vitro Test Using CaSR Expressing Cells

CaSR is a member of G protein-coupled receptor (GPCR). When CaSR ofcells are activated by stimulating with extracellular Ca²⁺ ion or anagonist (a compound having CaSR activating effect), etc., phospholipaseC (PLC) is activated through G protein (Gq), and an intracellularcalcium concentration is increased.

Thus, an activating effect on CaSR was examined by using CaSR expressingcell line and referring to change in an intracellular calciumconcentration as an index. Preparation of cell strains and a test usingthe same are, more specifically, carried out as mentioned in thefollowing (1) and (2).

(1) Acquisition of Human CaSR Expressing Cell Line

cDNA fragment encoding human CaSR was obtained from human kidney derivedcDNA library by PCR.

[Primer to be used for PCR was designed based on known nucleic acidsequence information on human CaSR

(GenBank/EMBL accession no. D50855; GenBank/EMBL accession no. NM000388;

Aida et al., Biochem. Biophys. Res. Commun., 214:524-529, 1995;

Garrett et al., J. Biol. Chem., 270: 12919-12925, 1995, etc.). Also, thefull length cDNA encoding CaSR was obtained first as three divisionalparts.]

These cDNA fragments were adequately connected to an expression vectorto obtain a plasmid for expressing a functional human CaSR in animalcells.

Also, this human CaSR expression plasmid was transfected to CHO cellswith a Gα16 expression plasmid [a plasmid which is to express α subunit(α16) of G protein], and selected from a medium containing neomycin(G418) to obtain stable expressing cell line.

The obtained cell line stably expressed CaSR of human and α16 subunit ofG protein.

(2) Measurement of Calcium Concentration in Cells

By using the CaSR expressing cell line obtained in the above-mentioned(1), change in an intracellular calcium concentration was measured atthe time when the cells were stimulated in the presence or in theabsence of a test compound as follows.

First, cells were collected using a cell scraper, suspended in asolution comprising Hepes buffer [10 mM Hepes (7.3), 10 mM glucose, 140mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂] to which 0.1% cremophor and 3μM Fura-2 had been added, and reacted at 37° C. for 1 hour under theconditions wherein a test compound of various concentrations (orconditions not added).

After being washed, the cells suspended in Hepes buffer were seeded to aplate (about 2×10⁵ cells per 1 well of 96-well plate), and fluorescentintensity (Ratio of 340/380 nm) was measured using FDSS (Functional DrugScreening System; Hamamatsu Photonics K.K.) to examine change inintracellular calcium concentrations.

CaSR activating effect was confirmed basing on the value (change in anintracellular calcium concentration) measured in the reaction carriedout in the presence of the test compound, a CaSR activating ability wasconfirmed.

Also, from the measured values (change in an intracellular calciumconcentration) of the test compound with various concentrations, aconcentration/response curve was drawn to obtain an EC50 value(concentration of agonist giving a half maximal response).

Experimental Example 2 Suppressing Effect on PTH Production

In Vitro Test Using Rat Parathyroid Cells

By using primary cultured cells prepared from the parathyroid in rats,suppressing effect on PTH production was examined according to thefollowing in vitro test.

(1) Preparation and Culture of Rat Parathyroid Cells:

Thirty-six 10-weeks old male CD (SD) IGS rats (Crj series, grade: SPF,CHARLES RIVER LABORATORIES JAPAN, INC.) were euthanasically sacrificedunder ether anesthesia, the thyroid gland together with the parathyroidglands were cut out under sterilized conditions, and preserved inITS-containing DMEM/F-12 medium (low Ca). The parathyroid glands wereseparated from the obtained material under observation by stereoscopicmicroscope, and collected in the same medium. Next, the medium wasdiscarded, the parathyroid glands were washed with a phosphate buffersolution (PBS(−)) containing no calcium and magnesium ions, 5 ml of acollagenase solution [PBS(−) containing 1.5 mg/ml of collagenase type IV(Gibco Co., catalogue No. 17104-019)] was added, and digested at 37° C.for 1 hour with shaking. After digestion, the enzyme solution wasdiscarded, the parathyroid glands were quickly minced with a scalpel ina laboratory dish, and were collected in 7 ml of a collagenase solution,and digested again at 37° C. for 90 minutes with shaking.

Cell debris was removed using cell strainer, the residue was removed,and then, the cells were collected. They were washed twice with anITS-containing DMEM/F-12 medium (low Ca) containing 5% FCS, andsuspended in the same medium. The parathyroid cells were suspended atthe concentration of about 5×10⁴ cells/ml, and were seeded to 96-wellplate (200 μl/well), and cultured (pre-culture) at 37° C. for about 24hours in a CO₂ incubator

The ITS-containing DMEM/F-12 medium (low Ca) to be used mentioned abovewas prepared as follows. Ca-free DMEM (Dulbecco's modified Eagle'smedium) (Gibco Co., catalogue No. 21068-028) (500 ml), F-12 (F-12nutrient mixture; Gibco Co., catalogue No. 11765-054) (500 ml) and 10 mlof ITS (a mixture containing 5 μg/ml of insulin, 5 μg/ml of transferrinand 5 ng/ml of selenium) (ITS+Premix; BD Biosciences Co., catalogue No.35435) were mixed. To the mixture was dissolved 3.5745 g of HEPES(NACALAI TESQUE Co., catalogue No. 17547-95), and 10 ml of 200 mML-glutamine (Gibco Co., catalogue No. 25030-081) and 1 ml ofPenicillin-Streptomycin solution (100× Penicillin-Streptomycin, liquid;Gibco Co., catalogue No. 15140-122) were added, and the resultingmixture was sterilized by filtration, and then, used. Ca concentrationin the medium is about 0.15 mM.

(2) Test of Suppressing Effect on PTH Production

Rat parathyroid cells were pre-cultured as mentioned in the above (1),then, the medium was changed, and the cells were cultured for 22 to 24hours in a medium to which a test compound and CaCl₂ had been added(96-well plate, 200 μl/well). Various concentrations of the testcompound and CaCl₂ were added to a serum-free ITS-containing DMEM/F-12medium (low Ca), and the resulting medium was used. When the testcompound is to be added, CaCl₂ was added so that the Ca concentrationbecame 1.15 mM. After culture, culture supernatant was collected, cells,etc. were removed therefrom by centrifugation, and was preserved at −80°C.

PTH (1-84) in the above-mentioned culture supernatant was measured bythe ELISA Method, and determined as a PTH production value. Measurementof PTH (1-84) was carried out by using a kit (Rat Intact PTH ELISA kit;Immutopics Co., catalogue No. 60-2500).

Based on the measured value (PTH production value), of the testcompounds, the inhibition rate in PTH production was calculated. In thecalculation, for the convenience sake, a PTH production value (A) inculture with 1.15 mM CaCl₂-containing medium (no test compound added)was set as a maximum production value, and a PTH production value (B) inculture with 2.15 mM CaCl₂-containing medium (no test compound added)was set as a minimum production, and inhibition rate was calculated fromthe following formula.Inhibition rate in PTH production (%)={(A)−(PTH production value in thepresence of 1.15 mM CaCl₂ and the test compound with variousconcentrations)}/{(A)−(B)}×100(when PTH production value obtained in the presence of the test compoundis the same as the maximum production level, then the inhibition rate is0%, and when it is the same as the minimum production level, then theinhibition rate is 100%.)

IC₅₀ value was measured from the PTH production-suppressing ratio in thepresence of the test compound with various kinds of concentrations.

IC₅₀ value was calculated by using a software for plotting aconcentration/response curve (Graphpad PRISM 3.0; Graphpad SoftwareCo.).

Experimental Example 3 Effect (I) on PTH Level in Blood

In Vivo Test Using Rat Adenine Model

As an animal model of hyperparathyroidism, rat adenine model was used,and an effect on a PTH level in blood (lowering effect on PTH in blood)was examined according to the following in vivo test.

Male CD (SD) IGS rats (10-weeks old or so) (Crj, grade: SPF, CHARLESRIVER LABORATORIES JAPAN, INC.) were used.

After acclimation for 7 days, during which rats were fed with standarddiet (CRF1), rats were provided with adenine diet (0.75%adenine-containing high phosphorus-low calcium diet (Ca: 0.5%, Pi:1.2%); supplied by Oriental Bioservice Inc.), and bred for 2 weeks.After 2 weeks, heparin-treated blood (250 μl) was collected from therespective rats under ether anesthesia. Blood was collected from jugularvein using 25 G (0.50×25 mm)-needle-tipped syringe, and after collectionof the blood, and then, subjected to astriction. Collected blood wascentrifuged at 12000 rpm for 3 minutes, and then, supernatant wascollected as a plasma sample.

PTH (PTH (1-84)) in the plasma was measured by ELISA.

PTH (1-84) was measured in the same manner as in item (2) of theabove-mentioned Experimental example 2.

Based on the results, rats in which a PTH concentration in blood wassufficiently raised were selected, and divided into groups such thataverage PTH concentration of each animal groups do not vary, andsubjected to the test.

On the next day, blood (400 μl) was collected prior to theadministration of the test compound, and then, the test compound wasorally administered. After 1, 4 and 24 hours following administration,400 μl of blood at each time point was collected, and plasma obtained bycentrifugation was preserved at −80° C. (or −20° C.).

PTH in the preserved plasma was measured in the same manner as mentionedabove.

According to this procedure, PTH-lowering effect of the test compoundwas confirmed.

Experimental Example 4 Effect (II) on PTH Level in Blood

In Vivo Test Using Rat Model of ⅚-Nephrectomy

Rat model of ⅚-nephrectomy was used as an animal model ofhyperparathyroidism. An effect on PTH level in blood (lowering effect onPTH in blood) was examined by the following in vivo test.

First, ⅚-nephrectomy was prepared as follows.

Male CD (SD) IGS rats (10-weeks old or so) (Crj, grade: SPF, CHARLESRIVER LABORATORIES JAPAN, INC.) were used.

A part (⅔) of rat's left kidney was removed, and one week after, theright kidney was removed.

After one week following the removal of the right kidney, rats wereprovided with high phosphorus-low calcium diet (Ca: 0.5%, Pi: 1.2%). Oneweek after the initiation of providing the high phosphorus-low calciumdiet, blood was collected from jugular vein to prepare a blood plasmasample. Body weight, and PTH, Ca, P and BUN concentrations in blood weremeasured, and the rats were divided into groups based on the resultsobtained.

Test compound was orally administered once a day to the animals preparedas mentioned above for two weeks, and blood was collected twice a weekimmediately before administration of the test compound. PTH, Ca, P andBUN concentrations in blood samples were measured.

According to this procedure, PTH-lowering effect of the test compoundwas confirmed.

Experimental Example 5 Pharmacological Effect of the Compounds of thePresent Invention

With respect to the compound of the present invention, in the samemanner as in the above-mentioned Experimental examples 2 and 3, theresults of measurement of the activating effect on CaSR and thesuppressing effect on PTH production were show in the following table.ACTIVITY TABLE Suppressing Activating effect effect on PTH Comound onCaSR production Example No. (EC₅₀ (μM)) (IC₅₀ (nM)) 1.077 0.42 5.3 3.0010.29 8 5.023 0.42 <10 12.020 0.018 0.27 12.028 0.017 0.47

Also, with regard to these compounds, in vivo test using rat adeninemodel was carried out in the same manner as in the above-mentionedExperimental example 4, and as a result, these compounds showed anlowering effect on PTH level in blood, in oral administration, ascompared with the control group in which no test compound to be testedwas administered.

Example 1.001

(1) To a suspension of 146.6 mg of(S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride,112.5 mg of 1-bromo-2-trifluoromethylbenzene, 22.5 mg of palladiumacetate, and 62.3 mg of BINAP(2,2′-bis(di-phenylphosphino-1,1′-binaphthyl)) in 5 ml of toluene wasadded 336 mg of sodium tert-butoxide, and the mixture was stirred at 80°C. for 16 hours. To the reaction mixture was added a saturated sodiumbicarbonate solution, the mixture was stirred and then the liquids wereseparated. The organic layer was dried and concentrated, and the residuewas purified by NH silica gel column chromatography (hexane:ethylacetate=97:3→80:20) to obtain 78.9 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]amine.(2) In 10 ml of chloroform was dissolved 78.9 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]amine,and 1 ml solution of 4M hydrochloric acid in a dioxane was added to themixture and the resulting mixture was stirred. The reaction mixture wasevaporated, and diethyl ether was added to the residue, and theprecipitates were collected by filtration and washed with diethyl etherto obtain 66.7 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(2-trifluoromethylphenyl)pyrrolidin-3-yl]aminedihydrochloride (the following Table A1, Example 1.001).

Examples 1.002 to 1.081

In the same manner as in the above-mentioned Example 1.001, compounds ofExample 1.002 to 1.081 in the following Table A1 were obtained.

Example 1.082

(1) In 2 ml of toluene were suspended 200 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride,127 mg of 4-bromoacetophenone, 214 mg of sodium tert-butoxide, and 76 mgof biphenyl-2-yl-di-tert-butylphosphane, and nitrogen gas was ventilatedfor 15 minutes. After adding 59 mg of tris(dibenzylideneacetone)dipalladium to the mixture, the reaction vessel was sealed and themixture was stirred at room temperature for 3 days. The reaction mixturewas diluted with ethyl acetate, and washed with a saturated aqueoussodium bicarbonate solution. The organic layer was separated andconcentrated, and the obtained residue was purified by silica gel columnchromatography to obtain(S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine.(2) In 2 ml of tetrahydrofuran was dissolved(S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amineobtained in the above-mentioned (1), and 0.2 ml of a solution of 4Mhydrochloric acid-dioxane was added to the mixture. The precipitatedsolids were collected by filtration, washed with ether and dried toobtain 90 mg of(S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminehydrochloride (the following Table A1, Example 1.082).

Example 1.083

In the same manner as in the above-mentioned Example 1.082, the compoundof Example 1.083 in the following Table A1 was obtained.

Example 2.001

(1) To a solution of 162 mg of(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and79.0 mg of 2,3-dichloro-pyrazine in 5 ml of ethanol was added 345 mg ofpotassium carbonate, and the mixture was stirred under reflux for 16hours. The reaction mixture was filtered, and the solvent wasevaporated, and to the residue was added a saturated aqueous sodiumbicarbonate solution and chloroform, and the liquids were separated. Theorganic layer was dried, and the solvent was evaporated, then, theresidue was purified by NH silica gel column chromatography(hexane:ethyl acetate=97:3→80:20) and by silica gel chromatography(hexane:ethyl acetate=90:10→0:100) to obtain 64.0 mg of(R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine.(2) In 2 ml of chloroform was dissolved 64.0 mg of(R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine,and 3 ml of a solution of 4M hydrochloric acid in dioxane was added tothe mixture, and the resulting mixture was stirred. After the reactionmixture was concentrated under reduced pressure, diethyl ether was addedto the residue, and the precipitates were collected by filtration,washed with diethyl ether, and dried to obtain 63.9 mg of(R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminedihydrochloride (the following Table A2, Example 2.001).

Examples 2.002 to 2.009

In the same manner as in the above-mentioned Example 2.001, thecompounds of Example 2.002 to 2.009 in the following Table A2 wereobtained.

Example 2.010

(1) To a suspension of 156.6 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in5 ml of dioxane were added 87.4 mg of 2-bromopyrimidine and 207 mg ofdiisopropylethylamine, and the mixture was stirred under reflux for 16hours. The reaction mixture was evaporated, and to the residue wereadded a saturated aqueous sodium bicarbonate solution and chloroform,the mixture was stirred and the liquids were separated. The organiclayer was dried, the solvent was evaporated, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=1:2→0:1) to obtain 112 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine.(2) In 10 ml of ethyl acetate was dissolved 112 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine,and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate wasadded to the mixture and the resulting mixture was stirred. The reactionmixture was concentrated under reduced pressure, to the residue wasadded diethyl ether, precipitates were collected by filtration andwashed with ethyl acetate, to obtain 68.3 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]aminedihydrochloride (the following Table A2, Example 2.010).

Examples 2.011 to 2.018

In the same manner as in the above-mentioned Example 2.010, thecompounds of Example 2.011 to 2.018 in the following Table A2 wereobtained.

Example 3.001

(1) In the same manner as in the above-mentioned Example 1.001,tert-butyl4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoate(the compound of Example 1.020 in the following Table A2) was obtained.(2) To a solution of 103 mg of tert-butyl4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoate in5 ml of a chloroform was added 20 ml of trifluoroacetic acid, and themixture was stirred under room temperature for 16 hours. The reactionmixture was concentrated, toluene was added to the residue and themixture was evaporated again. The residue was dissolved in 10 ml ofchloroform, 20 ml of a solution of 4M hydrochloric acid in dioxane wasadded and the mixture was stirred. The reaction mixture was concentratedunder reduced pressure, diethyl ether was added to the residue, andafter collecting the precipitates by filtration, it washed with diethylether and dried to obtain 89.2 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acidhydrochloride (Example 3.001 in the following Table A3).

Examples 3.002 to 3.011

In the same manner as in the above-mentioned Example 3.001, thecompounds of Example 3.002 to 3.011 in the following Table A3 wereobtained.

Example 3.012

(1) To a solution of 50 mg of4-[(S)-3-[(R)-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acidhydrochloride (the compound obtained in Example 3.001) in 5 ml ofmethylene chloride (MeOH free) was added dropwise 43 μl of oxalylchloride, and then, several drops of dimethylformamide were added to themixture, and the resulting mixture was stirred under room temperaturefor 16 hours. The solvent was removed from the reaction mixture toobtain the residue.(2) To the compound obtained as mentioned above were added dimethylamine(82 μl of 2M THF solution) and 10 ml of methylene chloride to dissolvethem, 70.2 μl of triethylamine was added to the mixture, and the mixturewas stirred under room temperature for 16 hours. To the reaction mixturewere added a saturated aqueous sodium bicarbonate solution andchloroform, the mixture was stirred and the liquids were separated. Theorganic layer was dried and concentrated, and the residue was purifiedby NH silica gel column chromatography (hexane:ethyl acetate 7:1→0:1) toobtain 22.4 mg ofN,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide.(3) To a solution of 22.4 mg ofN,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamidedissolved in 1 ml of methylene chloride was added dropwise 3 ml of asolution of 4M hydrochloric acid in dioxane, and the mixture was stirredfor a while. The reaction mixture was concentrated, t-butanol was addedto the residue to dissolve the same, and freeze-dried to obtain 22.9 mgofN,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-pyrrolidin-1-yl]benzamidehydrochloride (Example 3.012 in the following Table A3).

Examples 3.013 to 3.016

In the same manner as in the above-mentioned Example 3.012, thecompounds of Example 3.013 to 3.016 in the following Table A3 wereobtained.

Example 3.017

(1) To a mixed solution of 7.7 mg of 2-aminoethanol and 50 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acidhydrochloride (the compound obtained in Example 3.001) dissolved in 8 mlof dimethylformamide were added 22.2 mg of 1-hydroxybenzotriazole, 70 μlof triethylamine and 31.4 mg of EDC hydrochloride, and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasevaporated, a saturated aqueous sodium bicarbonate solution andchloroform were added to the residue, and the mixture was stirred andthe liquids were separated. The organic layer was dried andconcentrated, and the residue was purified by NH thin layer silica gelchromatography (chloroform:methanol=39:1) and thin layer silica gelchromatography (chloroform:methanol=9:1) to give 22.6 mg ofN-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide.(2) To a solution of 22.6 mg ofN-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamidedissolved in 1 ml of methylene chloride was added dropwise 3 ml of asolution of 4M hydrochloric acid in dioxane, and the mixture was stirredfor a while. The reaction mixture was evaporated; and, to the residuewas added tert-butanol to dissolve the same, and freeze-dried to obtain25.6 mg ofN-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamidehydrochloride (the following Table A3, Example 3.017).

Example 3.018

(1) In the same manner as in the above-mentioned Example 2.016,1-[(S)-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl]-(R)-1-(naphthalen-1-yl)ethylamine(a free form of the compound of Example 2.012 in the following Table)was obtained.(2) In 2 ml of toluene were suspended 100 mg of1-[(S)-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl]-(R)-1-(naphthalen-1-yl)ethylamine,52 mg of phenyl boronic acid and 78 mg of potassium carbonate, and anitrogen gas was ventilated for 5 minutes. After adding 32 mg oftetrakistriphenylphosphine palladium to the mixture, the reactionmixture was stirred under nitrogen flow at 100° C. overnight. Afterstanding to cool to room temperature, ethyl acetate and a saturatedaqueous sodium bicarbonate solution were added to the reaction mixture,and the liquids were separated. The organic layer was dried, the solventwas evaporated and the obtained residue was purified by silica gelcolumn chromatography (hexane-ethyl acetate) to obtain 46 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(6-phenylpyrimidin-4-yl)pyrrolidin-3-yl]amine.(3) In 1 ml of tetrahydrofuran was dissolved 46 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(6-phenylpyrimidin-4-yl)pyrrolidin-3-yl]amine,0.2 ml of a solution of 4M hydrochloric acid-dioxane was added, and themixture was allowed to stand at room temperature. The precipitatedsolids were collected by filtration, washed with ether, and dried toobtain 41 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(6-phenylpyrimidin-4-yl)pyrrolidin-3-yl]aminedihydrochloride (Example 3.018 in the following Table A3).

Examples 3.019 to 3.022

In the same manner as in the above-mentioned Example 3.018, thecompounds of Examples 3.019 to 3.022 in the following Table A3 wereobtained.

Example 4.001

(1) To a suspension of 176 mg of(S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride,110 mg of (3-trifluoromethyl)benzaldehyde and 636 mg of sodiumtriacetoxyborohydride in 10 ml of methylene chloride was added severaldrops of acetic acid, and the mixture was stirred at room temperaturefor 16 hours. To the reaction mixture were added a saturated aqueoussodium bicarbonate solution and chloroform, the mixture was stirred andthe liquids were separated. The organic layer was dried, the solvent wasremoved, and then, the residue was purified by NH silica gel columnchromatography (hexane:ethyl acetate=10:1) to obtain 91.2 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(3-trifluoromethylbenzyl)pyrrolidin-3-yl]amine.(2) In 10 ml of ethyl acetate was dissolved 91.2 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(3-trifluoromethylbenzyl)pyrrolidin-3-yl]amine,and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate wasadded, and the mixture was stirred. The reaction mixture was evaporated,diethyl ether was added to the residue, and after collecting theprecipitates by filtration, it washed with diethyl ether and dried toobtain 70.4 mg of(R)-1-(3-methoxyphenyl)ethyl-[(S)-1-(3-trifluoromethylbenzyl)pyrrolidin-3-yl]aminedihydrochloride (Example 4.001 in the following Table B).

Examples 4.002 to 4.038

In the same manner as in the above-mentioned Example 4.001, thecompounds of Examples 4.002 to 4.038 in the following Table B wereobtained.

Example 5.001

(1) After cooling a suspension of 156.6 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in5 ml of methylene chloride to 0° C., 208.6 mg of(3-trifluoromethyl)benzoyl chloride and 210 μl of triethylamine wereadded to the suspension, and the reaction mixture was stirred at roomtemperature for 1 hour. To the reaction mixture were added a saturatedaqueous sodium bicarbonate solution and chloroform, the mixture wasstirred and the liquids were separated. The organic layer was dried andconcentrated, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1→0:1) to obtain 210 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-1-(3-trifluoromethyl)benzoylpyrrolidine.MS·APCI (m/z) 413 [M+H]+(2) In 10 ml of chloroform was dissolved 210 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-1-(3-trifluoromethyl)benzoylpyrrolidine,1 ml of a solution of 4M hydrochloric acid in dioxane was added to thesolution and the mixture was stirred. The reaction mixture wasconcentrated under reduced pressure, diethyl ether was added to theresidue, and after collecting the precipitates by filtration, it waswashed with diethyl ether and dried to obtain 187.1 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-1-(3-trifluoromethyl)benzoylpyrrolidinehydrochloride (Example 5.001 in the following Table C).

Examples 5.002 to 5.016

In the same manner as in the above-mentioned Example 5.001, thecompounds of Examples 5.002 to 5.016 in the following Table C wereobtained.

Example 5.017

To solution of 125.3 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in5 ml of DMF were added 81.6 mg of (3-trifluoromethyl)phenylacetic acid,84.3 mg of 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimidehydrochloride, 67.3 mg of 1-hydroxybenzotriazole, and 153 μl oftriethylamine, and the reaction mixture was stirred at room temperaturefor 16 hours. To the reaction mixture were added a saturated aqueoussodium bicarbonate solution and ethyl acetate, the mixture was stirredand the liquids were separated. The organic layer washed with water andthen dried, the solvent was evaporated, and the residue was purified bythin layer silica gel chromatography (chloroform:methanol=19:1) toobtain 145.7 mg of(S)-3-[(R)-(naphthalen-1-yl)ethylamino]-1-(3-trifluoromethyl)phenylacetylpyrrolidine(Example 5.017 in the following Table C).

Examples 5.018 to 5.056

In the same manner as in the above-mentioned Example 5.017, thecompounds of Example 5.018 to 5.056 in the following Table C wereobtained.

Example 6.001

To a suspension of 94 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in5 ml of methylene chloride were added 56 mg of(3-trifluoromethyl)phenylisocyanate and 140 μl of triethylamine, thereaction mixture was stirred at room temperature for 16 hours. To thereaction mixture were added a saturated aqueous sodium bicarbonatesolution and chloroform, the mixture was stirred and the liquids wereseparated. The organic layer was dried, the solvent was evaporated, andthen, the residue was purified by thin layer silica gel chromatography(chloroform:methanol=19:1) to obtain 125.2 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-carboxylic acid(3-trifluoromethyl)phenylamide (Example 6.001 in the following Table).

Example 6.002

In the same manner as in the above-mentioned Example 6.001, thecompounds of Example 6.002 in the following Table C were obtained.

Example 7.001

(1) To a solution of 3.03 g of 3-hydroxypiperidine and 12.4 g of3-(trifluoromethoxy)phenyl boronic acid dissolved in 150 ml of methylenechloride were added 5.45 g of copper acetate hydrate, 7 ml oftriethylamine and 15 g of Molecular Sieve 4A (powder), and the mixturewas stirred at room temperature for 3 days. After the reaction mixturewas filtered, a saturated aqueous sodium bicarbonate solution andchloroform were added to the mixture and the mixture was stirred, then,insoluble materials were again filtered off. The filtrate was separated,the organic layer was dried and concentrated, and the residue waspurified by NH silica gel column chromatography (hexane:ethylacetate=10:1→2:1) to obtain 526 mg of1-(3-trifluoromethoxyphenyl)piperidin-3-ol. MS·APCI (m/z): 262 [M+H]+(2) 50 ml of a solution of 351 μl of oxalyl chloride in methylenechloride was cooled to −60° C., 357 μl of DMSO was added dropwise to thesolution, and the mixture was stirred at −60° C. for 10 minutes. To theabove mixture was added dropwise a solution of 526 mg of1-(3-trifluoromethoxyphenyl)piperidin-3-ol dissolved in 10 ml ofmethylene chloride, further 2.05 ml of triethylamine was added dropwiseto the above mixture, and then, the resulting mixture was stirred for 16hours while a temperature thereof was gradually raised to roomtemperature. To the reaction mixture were added a saturated aqueoussodium bicarbonate solution and chloroform, the mixture was stirred andthe liquids were separated. The organic layer was dried and concentratedto obtain 1-(3-trifluoromethoxyphenyl)piperidin-3-one.(3) To a solution of 158 mg of the compound obtained in theabove-mentioned (2) dissolved in 5 ml of methylene chloride was added85.6 mg of (R)-(+)-1-(1-naphthyl)ethylamine, the mixture was stirred atroom temperature for 1 hour, and then, 115 μl of acetic acid and 530 mgof sodium triacetoxy borohydride were added to the mixture, and themixture was stirred at room temperature for 16 hours. To the reactionmixture were added a saturated aqueous sodium bicarbonate solution andchloroform, the mixture was stirred and the liquids were separated. Theorganic layer was dried and the solvent was evaporated, then, theresidue was purified by thin layer silica gel chromatography(hexane:ethyl acetate=4:1) and thin layer NH silica gel chromatography(hexane:ethyl acetate=10:1→4:1) to obtain(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]amineand(R)-1-(naphthalen-1-yl)ethyl-[(R)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]amine,respectively.(4)(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]amineand(R)-1-(naphthalen-1-yl)ethyl-[(R)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]-amineobtained in the above-mentioned (3) were each dissolved in 10 ml ofethyl acetate, 1 ml of a solution of 4M hydrochloric acid in ethylacetate was added thereto and the mixture was stirred. The reactionmixture was concentrated under reduced pressure, diethyl ether was addedto the residue, the mixture washed and dried to obtain 23 mg of(R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]aminedihydrochloride (Example 7.001(a) in the following Table EF) and 38 mgof(R)-1-(naphthalen-1-yl)ethyl-[(R)-1-(3-trifluoromethoxyphenyl)piperidin-3-yl]aminedihydrochloride (Example 7.001(b) in the following Table), respectively.

Examples 7.002 to 7.007

In the same manner as in the above-mentioned Example 7.001, thecompounds of Examples 7.002 to 7.007 in the following Tables EF wereobtained.

Example 8.001

(1) To a solution of 2.61 g of 3-trifluoromethylbenzaldehyde dissolvedin 200 ml of methylene chloride was added 1.31 g of 3-pyrrolidinol, themixture was stirred at room temperature for a while, then 1.3 ml ofacetic acid and 4.77 g of sodium triacetoxy borohydride were added tothe mixture, and the mixture was stirred at room temperature for 15hours. To the reaction mixture was added a saturated aqueous sodiumbicarbonate solution to make it basic, and chloroform was added to themixture and the liquids were separated. The organic layer was dried andconcentrated to obtain 3.34 g of1-(3-trifluoromethylbenzyl)pyrrolidin-3-ol. MS·APCI (m/z): 246 [M+H]+(2) 100 ml of a solution of 2.38 ml of oxalyl chloride in methylenechloride was cooled to −60° C., 2.42 ml of DMSO was added dropwise tothe solution, and the mixture was stirred at −60° C. for 10 minutes. Tothe mixture was added dropwise a solution of 3.34 g of1-(3-trifluoromethylbenzyl)pyrrolidin-3-ol dissolved in 25 ml ofmethylene chloride, further 13.9 ml of triethylamine was added dropwisethereto, and the mixture was stirred for 16 hours while the temperaturethereof was gradually raised to room temperature. To the reactionmixture were added a saturated aqueous sodium bicarbonate solution andchloroform, the mixture was stirred and the liquids were separated. Theorganic layer was dried, the solvent was evaporated, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=5:1→2:1) to obtain 2.82 g of1-(3-trifluoromethylbenzyl)pyrrolidin-3-one. MS·APCI (m/z): 244 [M+H]+(3) To a solution of 507 mg of a1-(3-trifluoromethylbenzyl)pyrrolidin-3-one dissolved in 14 ml oftetrahydrofuran was added 320 mg of (R)-(+)-1-(1-naphthyl)ethylamine,and the mixture was stirred. T6 the mixed solution was added 800 mg oftitanium tetraisopropoxide, the mixture was stirred at room temperaturefor 15 hours, then, 105 mg of sodium borohydride and 3 ml of methanolwere added to the mixture, and the mixture was stirred at roomtemperature for 3.5 hours. To the reaction mixture was added aqueousammonia, the mixture was stirred, insoluble materials were filtered off,and the solvent was evaporated. To the residue were added chloroform andwater, the mixture was stirred and the liquids were separated. Theorganic layer was dried and concentrated, and the residue was purifiedby silica gel column chromatography (chloroform:methanol=50:1→9:1) andNH silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain443 mg of(R)-1-(naphthalen-1-yl)ethyl-[[1-(3-trifluoromethylbenzyl)pyrrolidine]-3-yl]amine(the following Table EF, Example 8.001). MS·APCI (m/z): 399 [M+H]+

Examples 8.002 to 8.011

In the same manner as in the above-mentioned Example 8.001, thecompounds of Examples 8.002 to 8.011 in the following Table EF wereobtained.

Examples 9.001 to 9.012

In the same manner as in the above-mentioned Example 5.017, thecompounds of Examples 9.001 to 9.012 in the following Table X wereobtained.

Examples 9.013 to 9.015

In the same manner as in the above-mentioned Example 5.001, thecompounds of Examples 9.013 to 9.015 in the following Table X wereobtained.

Examples 10.001 to 10.007

In the same manner as in the above-mentioned Example 1.082, thecompounds of Examples 10.001 to 10.007 in the following Table X wereobtained.

Examples 11.001 to 11.004

In the same manner as in the above-mentioned Example 3.001, thecompounds of Examples 11.001 to 11.004 in the following Table X wereobtained.

Examples 11.005 to 11.080

In the same manner as in the above-mentioned Example 3.017, thecompounds of Examples 11.005 to 11.080 in the following Table X wereobtained.

Example 12.001

To a solution of 157 mg of(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and120 mg of methyl 6-chloro-4-(trifluoromethyl)-nicotinate in 5 ml ofdioxane was added 346 mg of potassium carbonate, and the reactionsolution was stirred at 100° C. for 1 day. Further, to the reactionmixture was irradiated at 140° C. for 1 hour by using a Microwavereaction system, and then, the reaction mixture was cooled to roomtemperature. To the mixture were added water and ethyl acetate, and themixture was stirred and the liquids were separated. The organic layerwas dried and concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=80:20→50:50), and then, purified by NH thin layer silica gelcolumn chromatography (hexane:ethyl acetate=67:33) to obtain methyl6-[(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-4-trifluoromethylnicotinate(the following Table, Example, 12.001).

Example 12.002

(1) To 74.5 mg ofN-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-pyrrolidin-1-yl]benzoylglycinetert-butyl of Example 3.016 was added several drops of chloroform, anddissolved therein, and then, 10 ml of trifluoroacetic acid was added tothe mixture, and the resulting mixture was stirred at room temperaturefor 19 hours. The solvent was evaporated and the obtained residue waspurified by LC/MS, and further purified by silica gel thin-layerchromatography (chloroform:methanol:acetic acid=70:30:3) to obtainN-4-[(S)-3-[(R)-1-(naphthalen-1-yl)-ethylamino]-pyrrolidin-1-yl]benzoylglycine.(2) ToN-4-[(S)-3-[(R)-1-(naphthalen-1-yl)-ethylamino]-pyrrolidin-1-yl]benzoylglycineobtained by the above-mentioned (1) was added 4 ml of a solution of 4Mhydrochloric acid in dioxane, and the mixture was stirred for a while.The solvent was evaporated, and then toluene was added and evaporated.48 mg of the resulting pale yellowish powder was completely dissolved ina small amount of methanol and chloroform, and isopropyl ether was addedthereto to crystallize the product to obtain 41 mg ofN-4-[(S)-3-[(R)-1-(naphthalen-1-yl)-ethylamino]-pyrrolidin-1-yl]benzoylglycine hydrochloride (the following Table X, Example 12.002).

Example 12.003

(1) To a solution of 150 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acidhydrochloride of Example 3.001 and 58 mg of (1)-alanine methyl esterhydrochloride in 5 ml of DMF were added 163 mg of1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride, 115 mg of1-hydroxybenzotriazole and 125 μl of triethylamine, and the reactionmixture was stirred at room temperature for 1 day. To the reactionmixture were added water and ethyl acetate, the mixture was stirred andthen the liquids were separated. The organic layer was dried andconcentrated under reduced pressure, then, the residue was purified byNH silica gel column chromatography (hexane:ethyl acetate=65:35→35:65)to obtain 31.9 mg ofN—[(S)-1-methoxycarbonylethyl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide.

MS·APCI (m/z):446 [M+H]

(2) In 1 ml of THF was dissolved 31.9 mg ofN—[(S)-1-methoxycarbonylethyl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide,3.0 mg of lithium borohydride was added thereto, and the mixture wasstirred at room temperature for 1 day. To the reaction mixture was addeda saturated aqueous ammonium chloride solution, and chloroform was addedto the mixture and the mixture was stirred and then the liquids wereseparated. The organic layer was dried and evaporated, and then, theresidue was purified by NH silica gel thin-layer chromatography(chloroform:methanol=95:5) to obtain 14.7 mg ofN—[(S)-1-hydroxypropan-2-yl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide(the following Table X, Example 12.003).

Examples 12.004 to 12.008

In the same manner as in the above-mentioned Example 12.003, thecompounds of Examples 12.004 to 12.008 in the following Table X wereobtained.

Example 12.009

(1) To a solution of 200 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acidhydrochloride and 99.4 mg of (d)-proline methyl ester in 5 ml of DMFwere added 230 mg of 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimidehydrochloride, 162 mg of 1-hydroxybenzotriazole and 176 μl oftriethylamine, and the reaction mixture was stirred at room temperaturefor 1 day. To the reaction mixture were added water and ethyl acetate,the mixture was stirred and then the liquids were separated. The organiclayer was dried and concentrated under reduced pressure, and then, theresidue was purified by NH silica gel column chromatography(hexane:ethyl acetate=65:35→35:65) to obtain 161.0 mg of(d)-1-{4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoyl}prolinemethyl ester.

MS·APCI (m/z): 472 [M+H]

(2) In 3 ml of ethanol was dissolved 80.5 mg of(d)-1-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoyl]prolinemethyl ester, 171 μl of a 2N aqueous sodium hydroxide solution was addedto the solution, and the mixture was stirred at room temperature for 1day. After the reaction mixture was concentrated, 2 ml of water wasadded to the residue, and further 171 μl of 2N hydrochloric acid wasadded to the same. Precipitated solids were filtered and dried to obtain39.0 mg of(d)-1-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoyl]proline(the following Table X, Example 12.009).

Examples 12.010 to 12.016

In the same manner as in the above-mentioned Example 12.009, thecompounds of Examples 12.010 to 12.016 in the following Table X wereobtained.

Example 12.017

(1) To a solution of 150 mg of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and108 mg of 4-fluorophenylethylsulfone in 2 ml of DMSO was added 263 mg ofpotassium carbonate, and the reaction mixture was stirred at 130° C. for1 day. To the reaction mixture was added water and chloroform, themixture was stirred and the liquids were separated. The organic layerwas dried and evaporated, and then, the residue was purified by NHsilica gel column chromatography (hexane:ethyl acetate=80:20→40:60) toobtain 132.5 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]phenylethylsulfone.

MS·APCI (m/z):409[M+H]

(2) In a mixed solvent comprising 2 ml of ethyl acetate and 1 ml ofchloroform was dissolved 132.5 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]phenylethylsulfone,0.8 ml of a solution of 4N hydrogen chloride in dioxane was addedthereto, and the precipitated solids were filtered and dried. This wasrecrystallized from ethanol to obtain 40.0 mg of4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]phenylethylsulfonehydrochloride (the following Table X, Example 12.017).

Examples 12.018 to 12.023

In the same manner as in the above-mentioned Example 12.017, thecompounds of Examples 12.018 to 12.023 in the following Table X wereobtained.

Example 12.024

(1) In the same manner as in the above-mentioned Example 12.017,(S)-1-(4-methanesulfonyl-3-methoxycarbonyl)phenylpyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminewas obtained.(2) In 2 ml of tetrahydrofuran was dissolved 70 mg of(S)-1-(4-methanesulfonyl-3-methoxycarbonyl)phenylpyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine,0.32 ml of a 1N aqueous sodium hydroxide solution was added theretounder ice-cooling, and the mixture was stirred overnight while graduallyelevating the temperature to room temperature. Further, 0.32 ml of a 1Naqueous sodium hydroxide solution was added to the mixture, and themixture was stirred at room temperature for a half day and then heatedunder refluxing for 2 hours. After cooling the mixture to roomtemperature, the mixture was neutralized with 1N hydrochloric acid. Thereaction mixture was concentrated under reduced pressure, and theresulting solids were collected by filtration, washed with water andthen with diisopropyl ether, and dried to obtain 50 mg of(S)-1-(3-carboxy-4-methanesulfonyl)phenylpyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine(the following Table X, Example 12.024).

Examples 12.025 to 12.027

In the same manner as in the above-mentioned Example 12.024, thecompounds of Examples 12.025 to 12.027 in the following Table X wereobtained.

Example 12.028

(1) In the same manner as in the above-mentioned Example 1.082(1),(S)-1-(2-trityl-2H-tetrazol-5-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminewas obtained.

MS·APCI (m/z): 627 [M+H]+

(2) A mixture of 361 mg of(S)-1-(2-trityl-2H-tetrazol-5-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminein addition of 1 ml of water and a solution of 4M hydrochloricacid-dioxane was allowed to stand at room temperature for 4 hours. Tothe residue obtained by concentrated under reduced pressure, ethanol wasadded, and the mixture was again concentrated under reduced pressure. Tothe residue was added ether, and the solid was pulverized and collectedby filtration. By recrystallizing from ethanol, 185 mg of(S)-1-(1H-tetrazol-5-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminehydrochloride (the following Table X, Example 12.028) was obtained.

Example 12.029

In 1 ml of ethanol were dissolved 70 mg of(S)-1-(3-carboxy-1-oxopropyl)phenylpyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]aminewhich was obtained in the above-mentioned Example 12.025 and 8 μl ofhydrazine hydrate, and the mixture was heated under refluxing overnight.The mixture was cooled to room temperature, and, to a solid obtained byconcentration under reduced pressure were added 0.5 ml of ethyl acetateand 4 ml of ether. The solid was pulverized, collected by filtration,and dried to obtain 31 mg of(S)-1-(3-oxo-4,5-dihydro-2H-pyridazin-6-yl)phenylpyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine(the following Table X, Example 12.029).

Example 12.030

(1) Toluene was added to 4.37 g of(S)-1-(4-carboxyphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amineof the above-mentioned Example 1.001, 1.42 g of D-glucuronic acid allylester and 3.18 g of triphenylphosphine, and the mixture was concentratedunder reduced pressure and evaporated to dryness. To the mixture wasadded 100 ml of tetrahydrofuran, and to the mixture was added dropwise2.39 ml of diisopropyl azodicarboxylate over 10 minutes underice-cooling and stirring. The reaction mixture was stirred underice-cooling for 1 hour, and the residue obtained by concentration underreduced pressure was purified by silica gel column chromatography(chloroform/methanol) to obtain 715 mg of allyl2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]-aminopiperidin-1-yl]-benzoyl]-D-glucuronate.

MS·APCI (m/z): 577 [M+H]+

(2) In 6 ml of tetrahydrofuran was dissolved 615 mg of allyl2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronate,and the mixture was stirred under ice-cooling and in nitrogenatmosphere. To the mixture were added 91 μl of pyrrolidine, and then,123 mg of tetrakistriphenylphosphine palladium, and the resultingmixture was stirred for 30 minutes. The residue obtained byconcentration under reduced pressure was purified by LC-MS. Ether wasadded to the obtained solid, the solid was pulverized, collected byfiltration, and dried to obtain 220 mg of2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronicacid (Example 12.030 in the following Table X). (HPLC purity: 67.7%)

Example 12.031

(1) In the same manner as in Example 5.017,1-(4-methoxycarbonylphenoxyacetyl)-(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidinewas obtained.

MS·APCI (m/z): 433 [M+H]+

(2) To a solution of 250 mg of1-(4-methoxycarbonylphenoxyacetyl)-(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-pyrrolidinein 5 ml of an ethanol was added 0.64 ml of a 2N aqueous sodium hydroxidesolution, and the reaction mixture was stirred at room temperature for 5hours. Moreover, the mixture was heated under refluxing overnight, andthe reaction mixture was concentrated. 2 ml of water was added to theresidue, and 0.64 ml of 2N hydrochloric acid was further added to thesame and the precipitated solid was filtered and dried to obtain 26 mgof1-(4-carboxylphenoxyacetyl)-(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine(Example 12.031 in the following Table X).

Example 13.001

(1) A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml ofTHF was cooled to 0° C., and then, 100 ml of an aqueous 50%dimethylamine solution was added dropwise thereto, and the mixture wasstirred at room temperature for 1 day. To the reaction mixture wereadded water and ethyl acetate, the mixture was stirred and then theliquids were separated. The organic layer washed with a saturatedaqueous sodium bicarbonate solution and dried, the solvent wasevaporated, and diisopropyl ether and hexane were added to the residue.Then, the precipitates were collected by filtration and washed withhexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide.(2) In 600 ml of DMSO were suspended 25 g of(S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassiumcarbonate, and the mixture was stirred at 130° C. for 1 day. To thereaction mixture were added water and ethyl acetate, the resultingmixture was stirred and the liquids were separated. The organic layerwashed with water, and then dried, and the solvent was evaporated. Theresidue was dissolved in chloroform, NH silica gel was added thereto andthe mixture was allowed to stand for a while, and silica gel wasfiltered off. The silica gel was further washed with ethyl acetate. Thefiltrate and the washed solution were combined, and the residue obtainedby concentration under reduced pressure was purified by silica gelcolumn chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39g of tert-butyl[(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.

MS·APCI (m/z): 370 [M+H]+

(3) In ethyl acetate was dissolved 8.39 g of tert-butyl[(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]-carbamate, 200 ml ofa solution of 4M hydrochloric acid in ethyl acetate was added thereto,and the mixture was stirred at room temperature for 3 days. The solventwas evaporated, and then, diethyl ether was added to the residue, andthe precipitates were collected by filtration to obtain4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamidedihydrochloride. To the4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamidedihydrochloride were added a saturated aqueous sodium bicarbonatesolution and chloroform, the mixture was stirred and the liquids wereseparated. The organic layer was dried and concentrated under reducedpressure to obtain 5.85 g of4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide.

MS·APCI (m/z): 270 [M+H]+

(4) To a solution of 54 mg of4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide and 30 mgof 2-methoxyacetophenone in 1 ml of THF was added 85 mg of titaniumisopropoxide, and the mixture was stirred at room temperature for 1 day.Further, 12 mg of sodium borohydride was added to the reaction mixture,and then, 0.3 ml of methanol was added to the mixture, and the mixturewas stirred at room temperature for 4 hours. To the reaction mixture wasadded 0.5 ml of 28% aqueous ammonia solution, the mixture was stirred,and then, insoluble materials were removed and the solvent wasevaporated. The residue was purified by LC/MS to obtain 61 mg of4-[(S)-3-[1-(2-methoxyphenyl)ethylamino]pyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide.The4-[(S)-3-[1-(2-methoxyphenyl)ethylamino]pyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamidewas dissolved by adding 1 ml of tert-butanol, 0.15 ml of 2M aqueoushydrochloric acid was added thereto, and after stirring the mixture, itwas freeze-dried to obtain4-[(S)-3-[1-(2-methoxyphenyl)ethylamino]-pyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamidedihydrochloride (the following Table Y, Example 13.001).

Examples 13.002 to 13.003

In the same manner as in the above-mentioned Example 13.001, thecompounds of Examples 13.002 to 13.003 in the following Table Y wereobtained.

Reference Example 1.001

(1) To a solution of 8.0 g of (R)-1-benzyl-3-pyrrolidinol and 16.5 ml ofdiisopropylethylamine dissolved in 400 ml of methylene chloride wasadded dropwise a solution of 13.4 g of anhydroustrifluoromethanesulfonic acid in 50 ml of a methylene chloride at −20°C. or lower. The reaction mixture was stirred for 15 minutes whilemaintaining it to −20° C., then, a solution of 9.88 g of(R)-1-(3-methoxyphenyl)ethylamine in 100 ml of methylene chloride wasadded dropwise to the mixture at −20° C. or lower, and the reactionmixture was stirred at room temperature for 16 hours. To the reactionmixture were added a saturated aqueous sodium bicarbonate solution andchloroform, the mixture was stirred and the liquids were separated. Theorganic layer was dried and concentrated, and the residue was purifiedby silica gel column chromatography (chloroform:methanol=1:0→50:1) andNH silica gel column chromatography (hexane:ethyl acetate=25:1→10:1) toobtain 3.98 g of(S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine.

MS·APCI (m/z): 311 [M+H]+

(2) To a solution of 3.67 g of(S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]aminedissolved in 100 ml of methanol were added 830 mg of palladium hydroxideand 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and themixture was shaked under hydrogen atmosphere at 3 atm at roomtemperature for 3 days. Palladium hydroxide was removed, and the solventwas evaporated. To the residue was added methanol, and the resultingprecipitates were collected by filtration, washed with methanol anddried to obtain 1.14 g of(S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride(the following Reference example Table, Reference example 1.001).

Reference Example 1.002

(1) By using 8.0 g of (S)-1-benzyl-3-pyrrolidinol as a startingcompound, the same procedure was carried out as in Reference example1.001 (1) to obtain 4.36 g of(R)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine.

MS·APCI (m/z): 311 [M+H]+

(2) By using(R)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine, thesame procedure was carried out as in Reference example 1.001 (2) toobtain (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidinedihydrochloride (Reference example 1.002 in the following Referenceexample Table).

Reference Example 1.003

(1) To a solution of 25 g oftert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g ofdiisopropylethylamine dissolved in 500 ml of methylene chloride wasadded dropwise 100 ml of a solution of 49 g of anhydroustrifluoromethanesulfonic acid in methylene chloride at −20° C. or lower.The reaction mixture was stirred for 15 minutes while maintaining it to−20° C., and then, to the mixture was added dropwise 100 ml of asolution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylenechloride at −20° C. or lower, and the reaction mixture was stirred atroom temperature for 16 hours. To the reaction mixture were added asaturated aqueous sodium bicarbonate solution and chloroform, themixture was stirred and the liquids were separated. The organic layerwas dried and the solvent was evaporated, and the residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) toobtain 19.32 g of tert-butyl3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate.(2) To a solution of 19.32 g of tert-butyl3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolvedin 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloricacid in dioxane, and the mixture was stirred at room temperature for 16hours. The resulting precipitates were collected by filtration, washedwith ethyl acetate, and recrystallized from methanol and tetrahydrofurantwice to obtain 8.54 g of(R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride(the following Reference example Table, Reference example 1.003).

Reference Example 1.004

By using tert-butyl(R)-3-hydroxypyrrolidine-1-carboxylate, the sameprocedures were carried out as in Reference example 1.003 (1) and (2) toobtain (S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidinedihydrochloride (Reference example 1.004 in the following Referenceexample Table).

Reference Example 1.005

(1) To a solution of 25 g of tert-butyl3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylaminedissolved in 250 ml of methylene chloride was added dropwise a solutionof 49 g of anhydrous trifluoromethanesulfonic acid in 50 ml of methylenechloride at −20° C. or lower. The reaction mixture was stirred for 15minutes while maintaining it to −20° C., and to the mixture was addeddropwise 125 ml of a solution of 27.4 g of(R)-(+)-1-(1-naphthyl)ethylamine in methylene chloride at −20° C. orlower, and the reaction mixture was stirred at room temperature for 4.5hours. To the reaction mixture were added a saturated aqueous sodiumbicarbonate solution and chloroform, the mixture was stirred and theliquids were separated. The organic layer washed with water and asaturated brine, dried and the solvent was evaporated, and then, theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1→1:1) to obtain 25.8 g oftert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]-pyrrolidine-1-carboxylate.MS·APCI (m/z): 341 [M+H]+(2) To a solution of 36.3 g of triphosgene dissolved in 600 ml ofmethylene chloride was added dropwise a solution of 62.50 g oftert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylateand 76.4 ml of triethylamine in 250 ml of methylene chloride at −20° C.,and the mixture was stirred at room temperature for 1 hour. To thereaction mixture was added water, the mixture was stirred and theliquids were separated. The organic layer was dried, and the solvent wasevaporated. To the residue were added 1.48 L of tert-butanol and 50 mlof diisopropylethylamine, and the mixture was stirred at 70° C. for 16hours. The reaction mixture was evaporated, and the residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1→8:1) toobtain 24.98 g of tert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylateand 26.83 g oftert-butyl(R)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate,respectively.(3) To a solution of 28.9 g oftert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]-pyrrolidine-1-carboxylatedissolved in 60 ml of chloroform was added dropwise 116 ml of a solutionof 4M hydrochloric acid in dioxane, and the mixture was stirred at roomtemperature for 16 hours. The resulting precipitates were collected byfiltration, washed with diethyl ether, crystallized from ethanol-diethylether, washed with diethyl ether and dried to obtain 22.38 g of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride(Reference example 1.005(a) in the following Reference example Table).

Also, by using 21.8 g oftert-butyl(R)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate,the same procedure was carried out to obtain 15.92 g of(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride(the following Reference example 1.005(b)).

Reference Example 1.006

(1) To a solution of 14.9 g of triphosgene dissolved in 400 ml ofmethylene chloride was added dropwise a solution containing 25.68 g oftert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylate(the compound obtained in the above-mentioned Reference example 1.005(1)) and 31.5 ml of triethylamine in 100 ml of methylene chloride at−20° C. Further, 7.5 g of triphosgene was added to the same, and themixture was stirred at room temperature for 30 minutes. Water was addedto the reaction mixture, the mixture was stirred and the liquids wereseparated. The organic layer was dried, the solvent was evaporated, andthe residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1→2:1) to obtain 10.63 g oftert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylateand 9.22 g oftert-butyl(R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylateshown in the following Reference example Table, respectively.(2) To 18.52 g oftert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylatewas added 1.0 liter of tert-butanol, and the mixture was stirred at 60°C. for 2 days. The reaction mixture was concentrated, and then, theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to obtain 9.24 g oftert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate(the following Reference example 1.006(a)).

Also, by using 15.58 g oftert-butyl(R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate,the same procedure was carried out as mentioned above to obtain 7.03 goftert-butyl(R)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate(the following Reference example Table, Reference example 1.006(b)).

Reference Example 2.001

(1) 1-Benzhydrylazetidin-3-one was synthesized by the same method asdescribed in a literature (CHEM LETT 1999 (7) 605-606).

That is, to a solution of 27.27 g of 1-benzhydrylazetan-3-ol dissolvedin 225 ml of dimethylsulfoxide was added 135.5 ml of triethylamine,59.80 g of sulfur trioxide-pyridine complex was added thereto underice-cooling, and the mixture was stirred at room temperature for 2.5hours. To the reaction mixture were added water and ethyl acetate, themixture was stirred and the liquids were separated. The organic layerwashed with a saturated brine, dried and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1)to obtain 21.35 g of 1-benzhydrylazetidin-3-one.

(2) To a solution of 5.0 g of 1-benzohydrylazetidin-3-one dissolved in75 ml of toluene was added 2.98 ml of benzyloxycarbonyl chloride, andthe mixture was stirred at 80° C. for 4 hours. The reaction mixture wasevaporated, and then, to the residue were added water and ethyl acetate,the mixture was stirred and the liquids were separated. The organiclayer washed with water and a saturated brine, dried and concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=19:1→4:1), and then, hexane was added thereto, andafter collecting the precipitate by filtration, it washed with hexane toobtain 2.73 g of benzyl 3-oxoazetidine-1-carboxylate.

(3) To a solution of 8.51 g of benzyl 3-oxoazetidine-1-carboxylate and7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylenechloride, 7.49 g of magnesium sulfate was added to the solution. Themixture was stirred at room temperature for 3 hours, and then, 9.5 ml ofacetic acid and 13.18 g of sodium triacetoxy borohydride were addedthereto, and the mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added a saturated aqueous sodium bicarbonatesolution to make the mixture basic, chloroform was added to the same andthe mixture was stirred, and the liquids were separated. The organiclayer was dried and concentrated, and the residue was purified by NHsilica gel column chromatography (hexane:ethyl acetate=4:1→1:1) toobtain 7.90 g of benzyl3-[(R)-1-(naphthalen-1-yl)ethylamino]-azetidine-1-carboxylate.

(4) To a solution of 9.45 g of benzyl3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate dissolvedin 190 ml of methanol, 1 g of palladium carbon (10% wet) was addedthereto, and the reaction was carried out under hydrogen atmosphere atroom temperature for 4 hours. Palladium carbon was removed, the solventwas evaporated, and the residue was purified by NH silica gel columnchromatography (chloroform:methanol=1:0→19:1) to obtain 4.60 g of3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine. To a solution of 4.60 gof 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine dissolved in 30 ml ofethyl acetate, under ice-cooling, 13 ml of a solution of 4M hydrochloricacid in ethyl acetate was added dropwise, and the mixture was stirredfor a while.

After collecting the resulting precipitates by filtration, the productwas recrystallized from methanol and hexane, and washed with diethylether to obtain 5.86 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidinedihydrochloride (the following Reference example Table, Referenceexample 2.001).

Reference Example 3.001

(1) To a mixed solution containing 33.5 g of 3-hydroxypiperidine and62.7 ml of triethylamine dissolved in 250 ml of methylene chloride wasadded dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in150 ml of methylene chloride, and the mixture was stirred at roomtemperature for 16 hours. To the reaction mixture were added a saturatedaqueous citric acid and chloroform, the mixture was stirred and theliquids were separated. The organic layer was dried, the solvent wasevaporated, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl3-hydroxypiperidine-1-carboxylate. MS·APCI (m/z): 236 [M+H]+(2) 800 ml of a solution of 52.4 ml of oxalyl chloride in methylenechloride was cooled to −78° C., 53.2 ml of DMSO was added dropwise tothe solution, and the mixture was stirred at −78° C. for 0.5 hour. Asolution of 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate dissolvedin 200 ml of methylene chloride was added dropwise to the mixture, andfurther 293 ml of triethylamine was added dropwise to the same, and themixture was stirred for 16 hours while a temperature thereof wasgradually raised to room temperature. To the reaction mixture were addeda saturated aqueous sodium bicarbonate solution and chloroform, themixture was stirred and the liquids were separated. The organic layerwas dried and concentrated to obtain 83.7 g of1-benzyloxycarbonyl-3-piperidone. MS·APCI (m/z): 234 [M+H]+(3) To a solution of 83.7 g of 1-benzyloxycarbonyl-3-piperidonedissolved in 1.2 liters of methylene chloride was added 55.0 g of(R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred atroom temperature for 2 hours, 69 ml of acetic acid and 160 g of sodiumtriacetoxy borohydride were added to the mixture, and the mixture wasstirred at room temperature for 15 hours. To the reaction mixture wasadded an aqueous sodium hydroxide to make the mixture basic, and then,chloroform was added to the mixture, the mixture was stirred and theliquids were separated. The organic layer was dried and concentrated,and the residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1→0:1) to obtain 98.7 g of benzyl3-[(R)-1-(naphthalen-1-yl)ethylamino]-piperidine-1-carboxylate. MS·APCI(m/z): 389 [M+H]+(4) To a solution of 40.95 g of triphosgene dissolved in 800 ml ofmethylene chloride was added dropwise a mixed solution containing 80.6 gof benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylateand 86.6 ml of triethylamine dissolved in 200 ml of methylene chlorideat 0° C., and the mixture was stirred at room temperature for 16 hours.To the reaction mixture was added water, the mixture was stirred and theliquids were separated. The organic layer was dried and concentrated,and the residue washed with 200 ml of diethyl ether, and the crystalcollected by filtration was recrystallized from chloroform and diethylether to obtain 48.9 g ofbenzyl(R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

Further, the filtrate was purified by silica gel column chromatography(hexane:ethyl acetate=8:1→0:1) to obtain 5.82 g ofbenzyl(R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylateand 14.5 g ofbenzyl(S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

(5) To a solution containing 54.6 g ofbenzyl(R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylatedissolved in 700 ml of tetrahydrofuran was added 350 ml of water, andthe mixture was stirred under reflux for 15 hours. After tetrahydrofuranwas evaporated, a saturated aqueous sodium bicarbonate solution andchloroform were added thereto, the mixture was stirred and the liquidswere separated. The organic layer was dried and concentrated, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1→0:1) to obtain 24.3 g ofbenzyl(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

MS·APCI (m/z): 389 [M+H]+

(6) To a solution containing 24.2 g ofbenzyl(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylatedissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10%wet), and the mixture was shaked under hydrogen atmosphere at 3 atm atroom temperature for 40 hours. Palladium carbon was removed, and thesolvent was evaporated, the residue washed with ethyl acetate-chloroform(10:1), and collected by filtration to obtain 15.3 g of(R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-piperidine (the followingReference example Table, Reference example 3.001(a)). MS·APCI (m/z): 255[M+H]+

(7) By using 14.5 g ofbenzyl(S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate,the same treatment was carried out as in the above-mentioned (5) toobtain 4.74 g ofbenzyl(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.MS·APCI (m/z): 389 [M+H]+

Moreover, by using 4.7 g ofbenzyl(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate,the same treatment was carried out as in the above-mentioned (6) toobtain 2.89 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine.MS·APCI (m/z): 255 [M+H]+

(8) To a solution of 3.46 g of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dissolved in 15 mlof methanol was added dropwise 20 ml of a solution of 4M hydrochloricacid in ethyl acetate, and the mixture was stirred. The reaction mixturewas concentrated under reduced pressure, diethyl ether was added to theresidue, washed and dried to obtain 3.33 g of(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]-piperidine dihydrochloride(the following Reference example Table, Reference example 3.001(b)).MS·APCI (m/z): 255 [M+H]+ TABLE A1

Example No. R¹—X—

—Ar Salt Physical properties, etc. 1.001

2HCl MS·APCI: 365 [M + H] + 1.002

2HCl MS·APCI: 365 [M + H] + 1.003

2HCl MS·APCI: 365 [M + H] + 1.004

2HCl MS·APCI: 381 [M + H] + 1.005

2HCl MS·APCI: 385 [M + H] + 1.006

2HCl MS·APCI: 401 [M + H] + 1.007

Free form MS·APCI: 385 [M + H] + 1.008

2HCl MS·APCI: 385 [M + H] + 1.009

2HCl MS·APCI: 335 [M + H] + 1.010

2HCl MS·APCI: 335 [M + H] + 1.011

2HCl MS·APCI: 353 [M + H] + 1.012

2HCl MS·APCI: 342 [M + H] + 1.013

2HCl MS·APCI: 342 [M + H] + 1.014

2HCl MS·APCI: 331 [M + H] + 1.015

2HCl MS·APCI: 331 [M + H] + 1.016

2HCl MS·APCI: 351 [M + H] + 1.017

2HCl MS·APCI: 351 [M + H] + 1.018

2HCl MS·APCI: 351 [M + H] + 1.019

2HCl MS·APCI: 342 [M + H] + 1.020

Free form MS·APCI: 417 [M + H] + 1.021

Free form MS·APCI: 431 [M + H] + 1.022

2HCl MS·APCI: 401 [M + H] + 1.023

2HCl MS·APCI: 401 [M + H] + 1.024

2HCl MS·APCI: 318 [M + H] + 1.025

2HCl MS·APCI: 318 [M + H] + 1.026

2HCl MS·APCI: 318 [M + H] + 1.027

2HCl MS·APCI: 332 [M + H] + 1.028

2HCl MS·APCI: 332 [M + H] + 1.029

2HCl MS·APCI: 332 [M + H] + 1.030

2HCl MS·APCI: 332 [M + H] + 1.031

2HCl MS·APCI: 386 [M + H] + 1.032

2HCl MS·APCI: 386 [M + H] + 1.033

2HCl MS·APCI: 386 [M + H] + 1.034

2HCl MS·APCI: 386 [M + H] + 1035

Free form MS·APCI: 418 [M + H] + 1.036

2HCl MS·APCI: 319 [M + H] + 1.037

2HCl MS·APCI: 385 [M + H] + 1.038

2HCl MS·APCI: 401 [M + H] + 1.039

2HCl MS·APCI: 342 [M + H] + 1.040

2HCl MS·APCI: 331 [M + H] + 1.041

2HCl MS·APCI: 331 [M + H] + 1.042

2HCl MS·APCI: 331 [M + H] + 1.043

2HCl MS·APCI: 351 [M + H] + 1.044

2HCl MS·APCI: 385 [M + H] + 1.045

2HCl MS·APCI: 351 [M + H] + 1.046

2HCl MS·APCI: 351 [M + H] + 1.047

2HCl MS·APCI: 401 [M + H] + 1.048

Free form MS·APCI: 417 [M + H] + 1.049

2HCl MS·APCI: 318 [M + H] + 1.050

2HCl MS·APCI: 318 [M + H] + 1.051

2HCl MS·APCI: 343 [M + H] + 1.052

2HCl MS·APCI: 332 [M + H] + 1.053

2HCl MS·APCI: 332 [M + H] + 1.054

2HCl MS·APCI: 332 [M + H] + 1.055

2HCl MS·APCI: 352 [M + H] + 1.056

2HCl MS·APCI: 386 [M + H] + 1.057

2HCl MS·APCI: 386 [M + H] + 1.058

2HCl MS·APCI: 348 [M + H] + 1.059

2HCl MS·APCI: 319 [M + H] + 1.060

2HCl MS·APCI: 387 [M + H] + 1.061

2HCl MS·APCI: 349 [M + H] + 1.062

2HCl MS·APCI: 324 [M + H] + 1.063

2HCl MS·APCI: 356 [M + H] + 1.064

2HCl MS·APCI: 356 [M + H] + 1.065

2HCl MS·APCI: 356 [M + H] + 1.066

2HCl MS·APCI: 345 [M + H] + 1.067

2HCl MS·APCI: 345 [M + H] + 1.068

2HCl MS·APCI: 345 [M + H] + 1.069

2HCl MS·APCI: 365 [M + H] + 1.070

2HCl MS·APCI: 365 [M + H] + 1.071

2HCl MS·APCI: 365 [M + H] + 1.072

2HCl MS·APCI: 399 [M + H] + 1.073

2HCl MS·APCI: 399 [M + H] + 1.074

2HCl MS·APCI: 415 [M + H] + 1.075

2HCl MS·APCI: 415 [M + H] + 1.076

2HCl MS·APCI: 332 [M + H] + 1.077

2HCl MS·APCI: 332 [M + H] + 1.078

2HCl MS·APCI: 346 [M + H] + 1.079

2HCl MS·APCI: 346 [M + H] + 1.080

2HCl MS·APCI: 346 [M + H] + 1.081

2HCl MS·APCI: 333 [M + H] + 1.082

HCl MS·APCI: 359 [M + H] + 1.083

HCl MS·APCI: 371 [M + H] +

TABLE A2

Example No. R¹—X—

—Ar Salt Physical properties, etc. 2.001

2HCl MS·APCI: 353 [M + H] + 2.002

2HCl MS·APCI: 352 [M + H] + 2.003

2HCl MS·APCI: 353 [M + H] + 2.004

2HCl MS·APCI: 344 [M + H] + 2.005

2HCl MS·APCI: 400 [M + H] + 2.006

2HCl MS·APCI: 400 [M + H] + 2.007

2HCl MS·APCI: 357 [M + H] + 2.008

2HCl MS·APCI: 401 [M + H] + 2.009

2HCl MS·APCI: 358 [M + H] + 2.010

2HCl MS·APCI: 319 [M + H] + 2.011

2HCl MS·APCI: 353 [M + H] + 2.012

2HCl MS·APCI: 353 [M + H] + 2.013

2HCl MS·APCI: 318 [M + H] + 2.014

Free form MS·APCI: 319 [M + H] + 2.015

2HCl MS·APCI: 318 [M + H] + 2.016

2HCl MS·APCI: 353 [M + H] + 2.017

2HCl MS·APCI: 353 [M + H] + 2.018

2HCl MS·APCI: 353 [M + H] +

TABLE A3

Example No. R¹—X—

—Ar Salt Physical properties, etc. 3.001

HCl MS·APCI: 361 [M + H] + 3.002

HCl MS·APCI: 361 [M + H] + 3.003

HCl MS·APCI: 375 [M + H] + 3.004

HCl MS·APCI: 375 [M + H] + 3.005

HCl MS·APCI: 395 [M + H] + 3.006

HCl MS·APCI: 379 [M + H] + 3.007

HCl MS·APCI: 379 [M + H] + 3.008

2HCl MS·APCI: 375 [M + H] + 3.009

2HCl MS·APCI: 375 [M + H] + 3.010

2HCl MS·APCI: 375 [M + H] + 3.011

2HCl MS·APCI: 389 [M + H] + 3.012

2HCl MS·APCI: 388 [M + H] + 3.013

Free form 416MS·APCI: [M + H] + 3.014

3HCl MS·APCI: 473 [M + H] + 3.015

3HCl MS·APCI: 431 [M + H] + 3.016

Free form MS·APCI: 474 [M + H] + 3.017

2HCl MS·APCI: 404 [M + H] + 3.018

2HCl MS·APCI: 395 [M + H] + 3.019

2HCl MS·APCI: 429 [M + H] + 3.020

2HCl MS·APCI: 420 [M + H] + 3.021

2HCl MS·APCI: 479 [M + H] + 3.022

2HCl MS·APCI: 425 [M + H] +

TABLE B

Example No. R¹—X—

—Ar Salt Physical properties, etc. 4.001

2HCl MS·APCI: 379 [M + H] + 4.002

2HCl MS·APCI: 379 [M + H] + 4.003

2HCl MS·APCI: 345 [M + H] + 4.004

2HCl MS·APCI: 395 [M + H] + 4.005

2HCl MS·APCI: 399 [M + H] + 4.006

2HCl MS·APCI: 365 [M + H] + 4.007

2HCl MS·APCI: 415 [M + H] + 4.008

Free form MS·APCI: 431 [M + H] + 4.009

Free form MS·APCI: 431 [M + H] + 4.010

Free form MS·APCI: 431 [M + H] + 4.011

Free form MS·APCI: 399 [M + H] + 4.012

2HCl MS·APCI: 399 [M + H] + 4.013

Free form MS·APCI: 399 [M + H] + 4.014

2HCl MS·APCI: 365 [M + H] + 4.015

Free form MS·APCI: 365 [M + H] + 4.016

Free form MS·APCI: 365 [M + H] + 4.017

Free form MS·APCI: 349 [M + H] + 4.018

Free form MS·APCI: 345 [M + H] + 4.019

Free form MS·APCI: 345 [M + H] + 4.020

Free form MS·APCI: 356 [M + H] + 4.021

Free form MS·APCI: 361 [M + H] + 4.022

2HCl MS·APCI: 415 [M + H] + 4.023

Free form MS·APCI: 374 [M + H] + 4.024

Free form MS·APCI: 467 [M + H] + 4.025

Free form MS·APCI: 337 [M + H] + 4.026

Free form MS·APCI: 334 [M + H] + 4.027

Free form MS·APCI: 338 [M + H] + 4.028

Free form MS·APCI: 351 [M + H] + 4.029

Free form MS·APCI: 371 [M + H] + 4.030

Free form MS·APCI: 382 [M + H] + 4.031

Free form MS·APCI: 384 [M + H] + 4.032

Free form MS·APCI: 412 [M + H] + 4.033

Free form MS·APCI: 387 [M + H] + 4.034

2HCl MS·APCI: 351 [M + H] + 4.035

2HCl MS·APCI: 385 [M + H] + 4.036

2HCl MS·APCI: 401 [M + H] + 4.037

2HCl MS·APCI: 413 [M + H] + 4.038

2HCl MS·APCI: 429 [M + H] +

TABLE C

Example No. R¹—X—

—Ar Salt Physical properties, etc. 5.001

HCl MS·APCI: 413 [M + H] + 5.002

Free form MS·APCI: 413 [M + H] + 5.003

Free form MS·APCI: 413 [M + H] + 5.004

Free form MS·APCI: 345 [M + H] + 5.005

HCl MS·APCI: 429 [M + H] + 5.006

HCl MS·APCI: 429 [M + H] + 5.007

HCl MS·APCI: 429 [M + H] + 5.008

HCl MS·APCI: 429 [M + H] + 5.009

Free form MS·APCI: 413 [M + H] + 5.010

Free form MS·APCI: 367 [M + H] + 5.011

Free form MS·APCI: 435 [M + H] + 5.012

HCl MS·APCI: 361 [M + H] + 5.013

HCl MS·APCI: 391 [M + H] + 5.014

HCl MS·APCI: 375 [M + H] + 5.015

HCl MS·APCI: 375 [M + H] + 5.016

Free form MS·APCI: 374 [M + H] + 5.017

Free form MS·APCI: 427 [M + H] + 5.018

2HCl MS·APCI: 410 [M + H] + 5.019

2HCl MS·APCI: 348 [M + H] + 5.020

2HCl MS·APCI: 384 [M + H] + 5.021

2HCl MS·APCI: 398 [M + H] + 5.022

Free form MS·APCI: 359 [M + H] + 5.023

HCl MS·APCI: 427 [M + H] + 5.024

HCl MS·APCI: 427 [M + H] + 5.025

Free form MS·APCI: 427 [M + H] + 5.026

HCl MS·APCI: 495 [M + H] + 5.027

HCl MS·APCI: 377 [M + H] + 5.028

HCl MS·APCI: 377 [M + H] + 5.029

Free form MS·APCI: 377 [M + H] + 5.030

HCl MS·APCI: 395 [M + H] + 5.031

HCl MS·APCI: 393 [M + H] + 5.032

HCl MS·APCI: 393 [M + H] + 5.033

HCl MS·APCI: 393 [M + H] + 5.034

HCl MS·APCI: 427 [M + H] + 5.035

HCl MS·APCI: 373 [M + H] + 5.036

HCl MS·APCI: 389 [M + H] + 5.037

Free form MS·APCI: 365 [M + H] + 5.038

HCl MS·APCI: 365 [M + H] + 5.039

HCl MS·APCI: 365 [M + H] + 5.040

2HCl MS·APCI: 412 [M + H] + 5.041

2HCl MS·APCI: 398 [M + H] + 5.042

2HCl MS·APCI: 399 [M + H] + 5.043

HCl MS·APCI: 400 [M + H] + 5.044

HCl MS·APCI: 415 [M + H] + 5.045

HCl MS·APCI: 446 [M + H] + 5.046

HCl MS·APCI: 441 [M + H] + 5.047

HCl MS·APCI: 391 [M + H] + 5.048

HCl MS·APCI: 391 [M + H] + 5.049

HCl MS·APCI: 391 [M + H] + 5.050

HCl MS·APCI: 441 [M + H] + 5.051

HCl MS·APCI: 457 [M + H] + 5.052

2HCl MS·APCI: 412 [M + H] + 5.053

HCl MS·APCI: 387 [M + H] + 5.054

HCl MS·APCI: 389 [M + H] + 5.055

HCl MS·APCI: 437 [M + H] + 5.056

HCl MS·APCI: 457 [M + H] + 6.001

Free form MS·APCI: 428 [M + H] + 6.002

Free form MS·APCI: 428 [M + H] +

TABLE EF

Example No. R¹—X—

—Ar Salt Physical properties, etc. 7.001 (a)

2HCl MS·APCI: 415 [M + H] + 7.001 (b)

2HCl MS·APCI: 415 [M + H] + 7.002

Free form MS·APCI: 395 [M + H] + 7.003

Free form MS·APCI: 395 [M + H] + 7.004

2HCl MS·APCI: 399 [M + H] + 7.005

Free form MS·APCI: 401 [M + H] + 7.006

Free form MS·APCI: 385 [M + H] + 7.007

Free form MS·APCI: 381 [M + H] + 8.001

Free form MS·APCI: 399 [M + H] + 8.002

Free form MS·APCI: 415 [M + H] + 8.003

Free form MS·APCI: 365 [M + H] + 8.004

Free form MS·APCI: 379 [M + H] + 8.005

Free form MS·APCI: 395 [M + H] + 8.006

Free form MS·APCI: 345 [M + H] + 8.007

Free form MS·APCI: 429 [M + H] + 8.008

Free form MS·APCI: 379 [M + H] + 8.009

Free form MS·APCI: 393 [M + H] + 8.010

Free form MS·APCI: 409 [M + H] + 8.011

Free form MS·APCI: 359 [M + H] +

TABLE X

Example No. R¹—X—

—Ar Salt Physical properties, etc.  9.001

HCl MS·ESI: 413 [M + H] +  9.002

HCl MS·ESI: 429 [M + H] +  9.003

Free form MS·ESI: 415 [M + H] +  9.004

HCl MS·APCI: 407 [M + H] +  9.005

HCl MS·ESI: 427 [M + H] +  9.006

HCl MS·ESI: 427 [M + H] +  9.007

HCl MS·ESI: 377 [M + H] +  9.008

HCl MS·ESI: 377 [M + H] +  9.009

HCl MS·ESI: 365 [M + H] +  9.010

HCl MS·ESI: 379 [M + H] +  9.011

HCl MS·ESI: 441 [M + H] +  9.012

HCl MS·ESI: 389 [M + H] +  9.013

HCl MS·ESI: 375 [M + H] +  9.014

HCl MS·ESI: 389 [M + H] +  9.015

HCl MS·ESI: 374 [M + H] + 10.001

HCl MS·APCI: 356 [M + H] + 10.002

2HCl MS·APCI: 373 [M + H] + 10.003

2HCl MS·APCI: 373 [M + H] + 10.004

2HCl MS·APCI: 359 [M + H] + 10.005

2HCl MS·APCI: 385 [M + H] + 10.006

2HCl MS·APCI: 395 [M + H] + 10.007

HCl MS·APCI: 395 [M + H] + 11.001

Free form MS·APCI: 341 [M + H] + 11.002

Free form MS·APCI: 389 [M + H] + 11.003

Free form MS·APCI: 389 [M + H] + 11.004

Free form MS·APCI: 389 [M + H] + 11.005

2HCl MS·ESI: 360 [M + H] + 11.006

2HCl MS·ESI: 388 [M + H] + 11.007

2HCl MS·ESI: 414 [M + H] + 11.008

2HCl MS·ESI: 402 [M + H] + 11.009

2HCl MS·ESI: 416 [M + H] + 11.010

2HCl MS·ESI: 442 [M + H] + 11.011

2HCl MS·ESI: 432 [M + H] + 11.012

2HCl MS·ESI: 432 [M + H] + 11.013

2HCl MS·ESI: 446 [M + H] + 11.014

2HCl MS·ESI: 460 [M + H] + 11.015

2HCl MS·APCI: 418 [M + H] + 11.016

2HCl MS·ESI: 418 [M + H] + 11.017

2HCl MS·APCI: 418 [M + H] + 11.018

2HCl MS·APCI: 418 [M + H] + 11.019

2HCl MS·APCI: 432 [M + H] + 11.020

Free form MS·APCI: 432 [M + H] + 11.021

Free form MS·APCI: 458 [M + H] + 11.022

2HCl MS·ESI: 404 [M + H] + 11.023

2HCl MS·ESI: 432 [M + H] + 11.024

Free form MS·APCI: 458 [M + H] + 11.025

Free form MS·APCI: 458 [M + H] + 11.026

Free form MS·APCI: 434 [M + H] + 11.027

2HCl MS·APCI: 434 [M + H] + 11.028

Free form MS·APCI: 434 [M + H] + 11.029

Free form MS·APCI: 448 [M + H] + 11.030

2HCl MS·APCI: 462 [M + H] + 11.031

Free form MS·APCI: 460 [M + H] + 11.032

3HCl MS·ESI: 445 [M + H] + 11.033

2HCl MS·ESI: 445 [M + H] + 11.034

2HCl MS·ESI: 485 [M + H] + 11.035

3HCl MS·APCI: 445 [M + H] + 11.036

3HCl MS·ESI: 431 [M + H] + 11.037

3HCl MS·APCI: 487 [M + H] + 11.038

3HCl MS·ESI: 473 [M + H] + 11.039

2HCl MS·ESI: 525 [M + H] + 11.040

3HCl MS·ESI: 527 [M + H] + 11.041

3HCl MS·ESI: 471 [M + H] + 11.042

3HCl MS·ESI: 457 [M + H] + 11.043

3HCl MS·ESI: 487 [M + H] + 11.044

Free form MS·APCI: 521 [M + H] + 11.045

Free form MS·APCI: 471 [M + H] + 11.046

2HCl MS·ESI: 550 [M + H] + 11.047

2HCl MS·ESI: 549 [M + H] + 11.048

2HCl MS·ESI: 515 [M + H] + 11.049

2HCl MS·ESI: 444 [M + H] + 11.050

2HCl MS·ESI: 431 [M + H] + 11.051

2HCl MS·ESI: 487 [M + H] + 11.052

2HCl MS·ESI: 416 [M + H] + 11.053

2HCl MS·ESI: 388 [M + H] + 11.054

2HCl MS·ESI: 446 [M + H] + 11.055

2HCl MS·ESI: 432 [M + H] + 11.056

2HCl MS·ESI: 476 [M + H] + 11.057

2HCl MS·APCI: 418 [M + H] + 11.058

Free form MS·APCI: 448 [M + H] + 11.059

2HCl MS·ESI: 445 [M + H] + 11.060

2HCl MS·ESI: 471 [M + H] + 11.061

2HCl MS·ESI: 414 [M + H] + 11.062

2HCl MS·ESI: 458 [M + H] + 11.063

2HCl MS·APCI: 430 [M + H] + 11.064

Free form MS·APCI: 444 [M + H] + 11.065

2HCl MS·ESI: 521 [M + H] + 11.066

2HCl MS·ESI: 430 [M + H] + 11.067

2HCl MS·ESI: 507 [M + H] + 11.068

2HCl MS·ESI: 443 [M + H] + 11.069

3HCl MS·ESI: 443 [M + H] + 11.070

3HCl MS·ESI: 457 [M + H] + 11.071

2HCl MS·ESI: 471 [M + H] + 11.072

2HCl MS·ESI: 501 [M + H] + 11.073

2HCl MS·ESI: 521 [M + H] + 11.074

2HCl MS·APCI: 389 [M + H] + 11.075

2HCl MS·APCI: 417 [M + H] + 11.076

Free form MS·APCI: 405 [M + H] + 11.077

2HCl MS·APCI: 433 [M + H] + 11.078

2HCl MS·APCI: 419 [M + H] + 11.079

3HCl MS·APCI: 432 [M + H] + 11.080

3HCl MS·APCI: 474 [M + H] + 12.001

Free form MS·APCI: 444 [M + H] + 12.002

2HCl MS·APCI: 418 [M + H] + 12.003

Free form MS·APCI: 418 [M + H] + 12.004

Free form MS·APCI: 418 [M + H] + 12.005

Free form MS·APCI: 480 [M + H] + 12.006

HCl MS·APCI: 480 [M + H] + 12.007

HCl MS·APCI: 458 [M + H] + 12.008

HCl MS·APCI: 444 [M + H] + 12.009

Free form MS·APCI: 458 [M + H] + 12.010

Free form MS·APCI: 446 [M + H] + 12.011

Free form MS·APCI: 446 [M + H] + 12.012

Free form MS·APCI: 446 [M + H] + 12.013

Free form MS·APCI: 432 [M + H] + 12.014

Free form MS·APCI: 432 [M + H] + 12.015

Free form MS·APCI: 494 [M + H] + 12.016

Free form MS·APCI: 472 [M + H] + 12.017

HCl MS·APCI: 409 [M + H] + 12.018

Free form MS·APCI: 424 [M + H] + 12.019

Free form MS·APCI: 452 [M + H] + 12.020

3HCl MS·APCI: 467 [M + H] + 12.021

2HCl MS·APCI: 440 [M + H] + 12.022

2HCl MS·APCI: 454 [M + H] + 12.023

3HCl MS·APCI: 509 [M + H] + 12.024

Free form MS·APCI: 439 [M + H] + 12.025

Free form MS·APCI: 417 [M + H] + 12.026

Free form MS·APCI: 407 [M + H] + 12.027

Free form MS·APCI: 405 [M + H] + 12.028

HCl MS·APCI: 385 [M + H] + 12.029

Free form MS·APCI: 413 [M + H] + 12.030

Free form MS·APCI: 537 [M + H] + 12.031

Free form MS·APCI: 419 [M + H] +

TABLE Y

Example No. R¹—X—

—Ar Salt Physical properties, etc. 13.001

2HCl MS · APCI: 404 [M + H]+ 13.002

Free form MS · APCI: 388 [M + H]+ 13.003

2HCl MS · APCI: 430 [M + H]+

Reference Example Table

Reference Physical example properties, No. Structural formula Salt etc.1.001 1.004

2HCl MS · APCI: 221 [M + H]+ 1.002 1.003

2HCl MS · APCI: 221 [M + H]+ 1.005 (a)

2HCl MS · APCI: 241 [M + H]+ 1.005 (b)

2HCl MS · APCI: 241 [M + H]+ 1.006 (a)

Free form MS · APCI: 441 [M + H]+ 1.006 (b)

Free form MS · APCI: 441 [M + H]+ 2.001

2HCl MS · APCI: 228 [M + H]+ 3.001 (a)

Free form MS · APCI: 255 [M + H]+ 3.001 (b)

2HCl MS · APCI: 255 [M + H]+

1. An arylalkylamine compound represented by the formula [1-e]:

the symbols in the formula represent the following meanings: Ar:represents optionally substituted aryl or optionally substitutedheteroaryl, here, the cyclic portion of the heteroaryl is bicyclicheterocyclic ring in which 5- to 6-membered monocyclic heterocyclic ringcontaining 1 or 2 hetero atom(s) and benzene ring are fused; R¹:represents a group selected from the group consisting of optionallysubstituted cyclic hydrocarbon group, and optionally substitutedheterocyclic group; n: is an integer of 1 to 3; X: represents singlebonding arm, —CH₂—, —CO—, —(CH₂)_(m)—CO—, —CH(R²)—CO—,—(CH₂)_(p)—Y—(C(R³)(R⁴))_(q)—CO—, —NH—CO— or —N(R⁵)—CO—; in theabove-mentioned respective definitions of the X, the bonding armdescribed at the left end represents a bond with R¹; m is an integer of1 to 3; p is an integer of 0 to 2; q is an integer of 0 to 2; Y:represents —O— or —SO₂—; R²: represents phenyl or lower alkyl; R³, R⁴:each independently represents hydrogen atom or lower alkyl; R⁵:represents lower alkyl; provided that the ring portion of the grouprepresented by R¹ is neither naphthylidine nor partially saturated groupthereof, and, when X is —CH₂— or —CO—, R¹ is not naphthyl, or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein X is single bonding arm, —CO— or —(CH₂)_(m)—CO—.
 3. Thecompound according to claim 1, wherein n is 1 or 2, and X representssingle bonding arm, —CO— or —(CH₂)_(m)—CO—.
 4. The compound according toclaim 1, wherein n is 2, and X is single bonding arm.
 5. The compoundaccording to claim 1, wherein Ar is optionally substituted aryl.
 6. Thecompound according to claim 1, wherein Ar is optionally substitutedphenyl or optionally substituted naphthyl.
 7. The compound according toany one of claims 1 to 6, wherein Ar is a group which may be optionallysubstituted by group(s) selected from halogen, hydroxy, cyano,halo-lower alkyl, lower alkyl, lower alkoxy and lower alkylthio.
 8. Thecompound according to any one of claims 1 to 6, wherein Ar is a groupwhich may be optionally substituted by group(s) selected from loweralkyl and lower alkoxy.
 9. The compound according to claims 1 to 6,wherein the ring portion of the group represented by R¹ is cyclichydrocarbon group, or monocyclic heterocyclic group.
 10. The compoundaccording to claims 1 to 6, wherein the ring portion of the grouprepresented by R¹ is the following (i), (ii) or (iii): (i) monocyclic orbicyclic hydrocarbon group having 3 to 11 carbon atoms, which may besaturated partially or completely; (ii) monocyclic heterocyclic group,hetero ring of which comprises one saturated or unsaturated 5 to7-membered ring, and contains 1 to 4 hetero atom(s) selected fromnitrogen atom, oxygen atom and sulfur atom; or (iii) bicyclicheterocyclic group, hetero ring of which comprises two saturated orunsaturated 5 to 7-membered rings being fused, and contain 1 to 6 heteroatom(s) selected from nitrogen atom, oxygen atom and sulfur atom. 11.The compound according to claims 1 to 6, wherein the ring portion of thegroup represented by R¹ is the following (i), (ii) or (iii): (i)monocyclic or bicyclic hydrocarbon group selected from phenyl,cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, indanyl, indenyl,naphthyl, tetrahydronaphthyl, and partially or completely saturatedgroup thereof; (ii) monocyclic heterocyclic group selected frompyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxolanyl, thiolanyl,pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, furyl, oxazolyl, isooxazolyl, oxadiazolyl,thienyl, thiazolyl, isothiazolyl, thiadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyradinyl,pyridazinyl, pyranyl, perhydroazepinyl, perhydrothiazepinyl, partiallyor completely saturated group thereof, and a group in which the heteroatom(s) (N or S) thereof is/are oxidized; or (iii) bicyclic heterocyclicgroup selected from indolinyl, isoindolinyl, indolyl, indazolyl,isoindolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, benzodioxolanyl, benzothienyl, benzofuryl, thienopyridyl,thiazolopyridyl, pyrrolopyridyl, pyrrolopyrimidinyl,cyclopentapyrimidinyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, phthalazinyl, cinnolinyl, chromanyl, isochromanyl,benzothiazinanyl, partially or completely saturated group thereof, and agroup in which the hetero atom(s) (N or S) thereof is/are oxidized. 12.The compound according to claims 1 to 6, wherein the ring portion of thegroup represented by R¹ is the following (i) or (ii): (i) monocyclichydrocarbon group selected from phenyl, cyclohexyl, cyclopentyl,cyclobutyl and cyclopropyl; or (ii) monocyclic heterocyclic groupselected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxolanyl,thiolanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isooxazolyl,oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, piperidyl,piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl,pyradinyl, pyridazinyl, pyranyl, perhydroazepinyl, perhydrothiazepinyl,partially or completely saturated group thereof, and a group in whichthe hetero atom(s) (N or S) thereof is/are oxidized.
 13. The compoundaccording to claims 1 to 6, wherein the ring portion of the grouprepresented by R¹ is the following (i) or (ii): (i) monocyclichydrocarbon group selected from phenyl and cyclohexyl; or (ii)monocyclic heterocyclic group selected from pyrrolyl, thienyl,thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl,pyradinyl and pyridazinyl.
 14. The compound according to claims 1 to 6,wherein R¹ is cyclic hydrocarbon group optionally substituted bysubstituent(s) selected from the following Substituent group Q1 orheterocyclic group optionally substituted by substituent(s) selectedfrom the following Substituent group Q1: <Substituent Group Q1> halogencyano nitro oxo group hydroxy carboxy optionally substituted lower alkyl(which may be optionally substituted by 1 or plural groups selected fromhalogen, cyano, nitro, oxo, carboxy, hydroxy, lower alkoxy andhalo-lower alkoxy.) optionally substituted lower alkoxy (which may beoptionally substituted by 1 or plural groups selected from halogen,cyano, nitro, oxo, carboxy and hydroxy.) optionally substituted amino(which may be mono- or di-substituted by a group selected from loweralkyl, and halo-lower alkyl.) optionally substituted 5 to 6-memberedmonocyclic heterocyclic group (tetrazole, pyridazinyl, or partiallysaturated cyclic group thereof) (which may be optionally substituted by1 or plural groups selected from halogen, cyano, nitro, oxo, carboxy,hydroxy, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxyand acyl.) optionally substituted phenyl (which may be optionallysubstituted by 1 or plural groups selected from halogen, cyano, nitro,oxo, carboxy, hydroxy, lower alkyl, halo-lower alkyl, lower alkoxy,halo-lower alkoxy and acyl.) acyl.
 15. The compound according to any oneof claims 1 to 6, wherein when R¹ is optionally substituted phenyl, thesubstituent(s) is selected from carboxy, halogen, unsubstituted orsubstituted lower alkyl, unsubstituted or substituted lower alkoxy, acyland optionally substituted 5 to 6-membered monocyclic heterocyclicgroup.
 16. A method for treatment or prophylaxis of a disease whichcomprises administering to a patient an effective amount of the compoundaccording to claim
 1. 17. The method according to claim 16, wherein thedisease is a disease of which condition is expected to be improved byactivation of CaSR and/or suppression of PTH production.
 18. The methodaccording to claim 17, wherein the disease of which condition isexpected to be improved by activation of CaSR and/or suppression of PTHproduction is hyperparathyroidism.
 19. Use of the compound according toclaim 1 for manufacture of a medicament.
 20. The use according to claim19, wherein the medicament is for treatment or prophylaxis of a diseaseof which condition is expected to be improved by activation of CaSRand/or suppression of PTH production.
 21. The use according to claim 20,wherein the diseases of which condition is expected to be improved byactivation of CaSR and/or suppression of PTH production ishyperparathyroidism.
 22. A pharmaceutical composition containing thecompound according to claim 1 as an effective ingredient.
 23. Thepharmaceutical composition according to claim 22, wherein it is fortreatment or prophylaxis of a disease of which condition is expected tobe improved by activation of CaSR and/or suppression of PTH production.24. The pharmaceutical composition according to claim 23, wherein thedisease of which condition is expected to be improved by activation ofCaSR and/or repression of PTH production is hyperparathyroidism
 25. Amethod of assaying an effect of a test substance on PTH production,which comprises the steps of the following (i) to (iii): (i) preparingprimary culture parathyroid cells of rat, (ii) incubating the cells of(i) under conditions of low calcium concentration, in the presence ofvarious concentrations of a test substance, or, in the presence andabsence of the test substance, (iii) comparing PTH production level inthe presence of various concentrations of the test substance, orcomparing PTH production level in the presence and absence of the testsubstance, (iv) determining from the result of (iii) the strength of theeffect of the test substance on the PTH production, or presence orabsence of the effect of the same.